576:), resulting in graft reaction. However, there are two general cases in which an allograft may be accepted. One is when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance (like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in the brain). The second is when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection. Long-term exposure to a foreign antigen from fetal development or birth may result in establishment of central tolerance, as was observed in Medawar's mouse-allograft experiments. In usual transplant cases, however, such early prior exposure is not possible. Nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance. CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that dampen cytotoxic responses to grafted organs, are thought to play a role. In addition, genes involved in
656:. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers(epithelium barriers). Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both
425:, in immune tolerance was recognized in 1995 when animal models showed that CD4+ CD25+ T cells were necessary and sufficient for the prevention of autoimmunity in mice and rats. Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells. A more specific depletion and reconstitution experiment established the phenotype of these cells as CD4+ and CD25+. Later in 2003, experiments showed that Treg cells were characterized by the expression of the
966:
208:
instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system. Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution, tolerance does not refer to the change in the pathogen but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced
1108:
strains of mice fall neatly along a spectrum of being more tolerant but less resistant or more resistant but less tolerant. Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against
607:(MHC) proteins. However, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. Placental
957:
general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader. Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a
850:
hypersensitivity reactions have been mixed. The systemic effects of oral tolerance may be explained by the extensive recirculation of immune cells primed in one mucosal tissue in another mucosal tissue, allowing extension of mucosal immunity. The same probably occurs for cells mediating mucosal immune tolerance.
1103:
Evolution works to optimize host fitness, so whether elimination or tolerance occurs depends on which would benefit the organism most in a given scenario. If the antigen is from a rare, dangerous invader, the costs of tolerating its presence are high and it is more beneficial to the host to eliminate
973:
The advantages of immune tolerance, in particular, may be seen in experiments with mice infected with malaria, in which more tolerant mice have higher fitness at greater pathogen burdens. In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust
697:
is vulnerable to pathogenic penetration. The immune system must maintain its responsiveness to pathogenic antigens to prevent infections. The immune system has developed mechanisms in which orally ingested antigens can suppress following immune responses on a local and systemic level. Oral tolerance
734:
Dendritic cells play a crucial role in establishing oral tolerance for food antigens. The dendritic cells in the intestines cannot directly sample the antigens, as they are located behind the epithelial wall. There are different mechanisms in which the dendritic cells come in contact with the food
977:
Though it seems that the existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor, it comes with important evolutionary disadvantages. Some infectious microbes take advantage of existing mechanisms of tolerance to avoid
849:
reactions in certain cases. Records from 1829 indicate that
American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other
203:
In their Nobel
Lecture, Medawar and Burnet define immune tolerance as "a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response." Other more recent definitions have remained more or less the same. The 8th edition of Janeway's
432:
It was assumed that, since the presence of the Treg cells originally characterized was dependent on the neonatal thymus, these cells were thymically derived. By the mid-2000s, however, evidence was accruing of conversion of naïve CD4+ T cells to Treg cells outside of the thymus. These were later
278:
The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of
167:
twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Although Owen did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues.
956:
Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in
808:
and α4β7 expression. The mesenteric lymph node stromal cells also release retinoic acid and are required for gut localisation of the mesenteric lymph node T cell population. The differentiated regulatory T cells subsequently migrate to the lamina propria, where they multiply. CX3CR1+ macrophages
282:
This process of negative selection ensures that T and B cells that could initiate a potent immune response to the host's own tissues are eliminated while preserving the ability to recognize foreign antigens. It is the step in lymphocyte education that is key for preventing autoimmunity (entire
216:
Immune tolerance is formally differentiated into central or peripheral; however, alternative terms such as "natural" or "acquired" tolerance have at times been used to refer to establishment of tolerance by physiological means or by artificial, experimental, or pharmacological means. These two
1107:
Despite having mechanisms for both immune resistance and tolerance, any one organism may be overall more skewed toward a tolerant or resistant phenotype depending on individual variation in both traits due to genetic and environmental factors. In mice infected with malaria, different genetic
207:
Immune tolerance encompasses the range of physiological mechanisms by which the body reduces or eliminates an immune response to particular agents. It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection
298:
develops after T and B cells mature and enter the peripheral tissues and lymph nodes. It is established by a number of partly overlapping mechanisms that mostly involve control at the level of T cells, especially CD4+ helper T cells, which orchestrate immune responses and give B cells the
602:
The fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. Women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and
1004:. The injection of Treg cells specific for a tumor antigen also can reverse experimentally-mediated tumor rejection based on that same antigen. The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.
178:"We did not set out with the idea in mind of studying the immunological consequences of the phenomenon described by Owen; on the contrary, we had been goaded by Dr. H.P. Donald into trying to devise a foolproof method of distinguishing monozygotic from dizygotic twins... ."
299:
confirmatory signals they need in order to produce antibodies. Inappropriate reactivity toward normal self-antigen that was not eliminated in the thymus can occur, since the T cells that leave the thymus are relatively but not completely safe. Some will have receptors (
267:, a state of non-activity. Weakly autoreactive B cells may also remain in a state of immunological ignorance where they simply do not respond to stimulation of their B cell receptor. Some weakly self-recognizing T cells are alternatively differentiated into natural
787:
After antigen interaction the CD103+ dendritic cells travel to the mesenteric lymph nodes where they interact with their T cell population. Within the mesenteric lymph nodes the CD103+ dendritic cells will induce differentiation of the naïve T cell population into
172:
in 1953, who showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as
Medawar explains:
256:. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor
212:
by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non-reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed.
888:. Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic
816:
In the lamina propria the regulatory T cell population creates a tolerogenic environment to food antigens. It is known that tolerance to food antigens is systemic. The mechanism that establishes this systemic tolerance is not yet fully understood.
961:
of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data. Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described.
1012:
Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead.
1016:
Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite. Each strategy has its unique costs and benefits for host fitness:
330:
Appropriate reactivity toward certain antigens can also be quieted by induction of tolerance after repeated exposure, or exposure in a certain context. In these cases, there is a differentiation of naïve CD4+ helper T cells into induced
693:. The intestine harbours many non-self-antigens that are able to induce an immune reaction. The immune system in the gut needs to restrain from responding to these antigens to prevent constant inflammation. On the other hand, the thin
908:, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as
433:
defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells. Both types of Treg cells quieten autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms including:
639:
to reactive T cells These mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. A break in this peripheral tolerance results in miscarriage and fetal loss. (for more information, see
664:
efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining. Break in this tolerance is thought to underlie the pathogenesis of
2445:
Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. (May 2007). "T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells".
287:). Lymphocyte development and education is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.
1104:
it. Conversely, if experience (of the organism or its ancestors) has shown that the antigen is innocuous, then it would be more beneficial to tolerate the presence of the antigen rather than pay the costs of inflammation.
322:
Those self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively muzzled in the peripheral tissue chiefly by nTreg cells (see
217:
methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind.
948:(MDSCs), which also induce peripheral tolerance. In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.
916:, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including
102:
2092:
Maher S, Toomey D, Condron C, Bouchier-Hayes D (April 2002). "Activation-induced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack".
860:
in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually,
228:
refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the
183:
However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by
558:
nTreg cells are specific, modestly, for self-antigen while iTreg cells recognize allergens, commensal bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.
361:
are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells, including
775:
extend in between enterocytes and directly take up antigens form the intestinal lumen. These macrophages are not capable of traveling to the mesenteric lymph nodes. They form
279:
pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.
3325:
Kretschmer K, Apostolou I, Jaeckel E, Khazaie K, von
Boehmer H (August 2006). "Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer".
3282:
Ghiringhelli F, Ménard C, Martin F, Zitvogel L (December 2006). "The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression".
1000:, and other worms and parasites. Another important disadvantage of the existence of tolerance may be susceptibility to cancer progression. Treg cells inhibit anti-tumor
796:
instead. The local microenvironment determines if CD103+ dendritic cells act tolerogenic or immunogenic. The differentiation into regulatory T cells is dependent on
249:
837:
from the liver and mesenteric lymph node can induce anergy or deletion of antigen specific T cells. Anergic T cells are hyporesponsive to their specific antigen.
263:
Those lymphocytes that have receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of
195:. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.
147:
that manage to evade immune elimination. Additionally, the induction of peripheral tolerance within the local microenvironment is a strategy employed by many
42:
and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either
3481:
623:, which represses maternal T cell responses by amino acid starvation. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic
969:
Schematic of the reaction norm of tolerance (after). Organisms of genotype 2 are considered more tolerant to the pathogen than organisms of genotype 1.
1412:"Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases"
726:. The newly differentiated regulatory T cells travel to the lamina propria, where they suppress the immune reaction against the recognized antigens.
572:
Immune recognition of non-self-antigens typically complicates transplantation and engrafting of foreign tissue from an organism of the same species (
940:. Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer. Tumor-derived vesicles known as
62:. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.
525:
nTreg cells and iTreg cells, however, have a few important distinguishing characteristics that suggest they have different physiological roles:
3368:
Råberg L, Sim D, Read AF (November 2007). "Disentangling genetic variation for resistance and tolerance to infectious diseases in animals".
652:
The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the
2671:"All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation"
829:
or deletion of antigen specific T cells. This process can take place in the liver. The liver is exposed to many food antigens through the
715:
544:
nTreg cells develop from Foxp3- CD25+ CD4+ cells while iTreg cells develop from Foxp3+ CD25- CD4- cells (both become Foxp3+ CD25+CD4+).
912:, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing
69:. Central tolerance is crucial for enabling the immune system to differentiate between self and non-self antigens, thereby preventing
489:
98:
377:
cells, as well as other less well-characterized cells that help establish a local tolerogenic environment. B cells also express
3474:
2581:"Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1⁺ macrophages to CD103⁺ dendritic cells"
1657:
Fenner F (June 1983). "The Florey lecture, 1983. Biological control, as exemplified by smallpox eradication and myxomatosis".
2874:
1925:
1641:
1240:
362:
73:. Peripheral tolerance plays a significant role in preventing excessive immune reactions to environmental agents, including
869:
685:
Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut
410:
3467:
3117:"The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells"
1989:
Vadasz Z, Haj T, Kessel A, Toubi E (June 2013). "B-regulatory cells in autoimmunity and immune mediated inflammation".
1183:
381:, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes
3440:
271:(nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see
1946:
Sakaguchi S, Miyara M, Costantino CM, Hafler DA (July 2010). "FOXP3+ regulatory T cells in the human immune system".
1361:"Expression of the autoimmune regulator gene and its relevance to the mechanisms of central and peripheral tolerance"
284:
245:
401:
in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs. In addition,
3813:
604:
880:, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in
945:
797:
769:
657:
507:
386:
370:
344:
397:
needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce
3808:
974:
commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.
690:
538:
455:
1860:
Hogquist KA, Baldwin TA, Jameson SC (October 2005). "Central tolerance: learning self-control in the thymus".
3751:
3072:
Ramsay AG (August 2013). "Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity".
2176:
Braza F, Soulillou JP, Brouard S (September 2012). "Gene expression signature in transplantation tolerance".
641:
597:
191:, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed
143:
However, immune tolerance is not without its drawbacks. It can permit the successful infection of a host by
2769:"Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria"
1149:
86:
2808:
Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, et al. (September 2008).
529:
nTreg cells develop in the thymus; iTreg cells develop outside the thymus in chronically inflamed tissue,
1710:"Studies on the mechanism of the immunological paralysis induced in mice by pneumococcal polysaccharides"
917:
834:
620:
390:
1129:
3637:
1117:
666:
114:
105:(IPEX) as examples. Furthermore, disruptions in immune tolerance are implicated in the development of
3459:
2720:"Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo"
3453:
2866:
2767:
Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, et al. (February 2011).
1917:
1633:
1232:
481:
336:
762:. Goblet cell-associated antigen passages (GAP) transfer low molecular weight soluble antigens to
584:
function associated with tolerance have been implicated for liver transplant patients. The unique
3817:
3575:
929:
612:
352:
310:
the T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the
307:
are present in such high concentration outside the thymus that they can bind to "weak" receptors.
244:, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by
184:
2260:
Clark DA, Chaouat G (December 2012). "Regulatory T cells and reproduction: how do they do it?".
3839:
3557:
3493:
1764:"Mechanisms of natural tolerance in the intestine: implications for inflammatory bowel disease"
990:
913:
792:
regulatory T cells (iTregs). Under inflammatory conditions, CD103+ dendritic cells will induce
752:
3786:
3642:
3620:
694:
627:
and activated iTregs or cross-reacting nTregs. Some maternal Treg cells also release soluble
339:(lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by
3449:
2858:
2622:"Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells"
2530:
McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA, et al. (March 2012).
1909:
1625:
1224:
755:
surface of the enterocytes. Here dendritic cells can interact with the presented antigens.
3803:
3736:
3647:
3571:
3377:
3182:
2718:
Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Förster R, Pabst O (October 2008).
1998:
1666:
1139:
804:. Retinoic acid is also programming the T cells to stay in the gut environment by inducing
636:
315:
311:
295:
257:
204:
Immunobiology defines tolerance as "immunologically unresponsive...to another's tissues.".
90:
55:
1521:"Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?"
8:
3910:
3863:
3798:
3781:
3615:
3533:
2859:
1910:
1626:
1225:
1001:
984:
616:
577:
573:
429:
transcription factor, which is responsible for the suppressive phenotype of these cells.
144:
82:
3381:
3239:
Philosophical
Transactions of the Royal Society of London. Series B, Biological Sciences
3186:
2002:
1817:
Philosophical
Transactions of the Royal Society of London. Series B, Biological Sciences
1670:
1593:
1568:
168:
This observation was experimentally validated by Leslie Brent, Rupert E. Billingham and
3683:
3411:
3350:
3307:
3259:
3234:
3203:
3170:
3141:
3116:
3097:
3049:
3024:
3005:
2921:
2890:
Soyer OU, Akdis M, Ring J, Behrendt H, Crameri R, Lauener R, Akdis CA (February 2013).
2834:
2809:
2744:
2719:
2695:
2670:
2646:
2621:
2556:
2532:"Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine"
2531:
2507:
2482:
2373:
2348:
2321:
2296:
2239:
2117:
2066:
2041:
2022:
1971:
1885:
1837:
1812:
1793:
1739:
1690:
1606:
1485:
1460:
1436:
1411:
1387:
1360:
1336:
1311:
1282:
1257:
674:
670:
588:
of these patients implies their physiology may be predisposed toward immune tolerance.
2422:
2397:
34:'s state of unresponsiveness to substances or tissues that would otherwise trigger an
3731:
3497:
3403:
3342:
3338:
3299:
3295:
3264:
3208:
3146:
3089:
3054:
2997:
2962:
2913:
2870:
2839:
2790:
2749:
2700:
2651:
2602:
2561:
2512:
2498:
2463:
2427:
2378:
2326:
2277:
2243:
2231:
2193:
2158:
2109:
2105:
2071:
2014:
1963:
1921:
1877:
1842:
1785:
1780:
1763:
1731:
1682:
1637:
1598:
1542:
1490:
1441:
1392:
1341:
1287:
1236:
979:
941:
885:
861:
833:
and is therefore also a site of food tolerance induction. Upon high antigen exposure
723:
422:
358:
332:
268:
253:
225:
209:
43:
3415:
3354:
3311:
3009:
2925:
2121:
2026:
1975:
1743:
1694:
1610:
3851:
3791:
3763:
3758:
3713:
3703:
3393:
3385:
3334:
3291:
3254:
3246:
3198:
3190:
3136:
3128:
3101:
3081:
3044:
3036:
2989:
2952:
2903:
2829:
2821:
2780:
2739:
2731:
2690:
2682:
2641:
2633:
2592:
2551:
2543:
2502:
2494:
2455:
2417:
2409:
2368:
2360:
2316:
2308:
2269:
2223:
2185:
2148:
2101:
2061:
2053:
2006:
1955:
1869:
1832:
1824:
1797:
1775:
1721:
1674:
1588:
1580:
1532:
1480:
1472:
1431:
1423:
1382:
1372:
1331:
1323:
1277:
1269:
857:
846:
510:, which sensitizes cells to suppression and promotes Treg-like cell differentiation
406:
2483:"Enterocytes: active cells in tolerance to food and microbial antigens in the gut"
2010:
1889:
3746:
3444:
2825:
2785:
2768:
2597:
2580:
2459:
2312:
2227:
1537:
1520:
1427:
865:
766:
dendritic cells. CD103+ dendritic cells are associated with tolerance induction.
686:
581:
374:
300:
192:
94:
35:
81:. Deficiencies in either central or peripheral tolerance mechanisms can lead to
3773:
3718:
3659:
3579:
3552:
2398:"Oral tolerance, an active immunologic process mediated by multiple mechanisms"
1327:
965:
896:
to cause allergic reactions, can also reduce antibiotic allergies in children.
810:
711:
707:
624:
585:
514:
382:
348:
78:
2273:
2189:
1584:
1273:
3904:
3741:
3630:
1726:
1709:
1134:
996:
958:
826:
801:
793:
661:
340:
169:
31:
3389:
3194:
2153:
2136:
2135:
Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T (October 2009).
845:
The hypo-responsiveness induced by oral exposure is systemic and can reduce
3708:
3693:
3688:
3625:
3523:
3437:
3407:
3346:
3303:
3268:
3250:
3212:
3150:
3093:
3058:
3001:
2980:
Cernadas JR (February 2013). "Desensitization to antibiotics in children".
2966:
2917:
2843:
2794:
2753:
2704:
2655:
2606:
2565:
2516:
2467:
2431:
2382:
2330:
2281:
2235:
2197:
2162:
2113:
2075:
2018:
1967:
1908:
Murphy K (2012). "Chapter 8: The
Development and Survival of Lymphocytes".
1881:
1846:
1828:
1789:
1735:
1678:
1602:
1546:
1494:
1445:
1396:
1345:
1291:
1144:
1109:
937:
909:
813:, which is required for the expansion of the regulatory T cell population.
776:
744:
466:
188:
70:
2637:
1686:
1377:
1312:"Coordination of tolerogenic immune responses by the commensal microbiota"
779:
with CD103+ dendritic cells and transfer antigens to the dendritic cells.
2735:
2686:
2214:
Gökmen R, Hernandez-Fuentes MP (August 2013). "Biomarkers of tolerance".
1659:
Proceedings of the Royal
Society of London. Series B, Biological Sciences
830:
759:
698:
may have evolved to prevent hypersensitivity reactions to food proteins.
608:
233:
160:
137:
66:
59:
51:
2957:
2940:
2547:
3831:
3584:
3490:
944:
have also been implicated promoting differentiation of iTreg cells and
925:
877:
772:
736:
653:
632:
530:
402:
394:
133:
3235:"Decomposing health: tolerance and resistance to parasites in animals"
3132:
3115:
Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ (February 2013).
3085:
3023:
Aktipis CA, Boddy AM, Gatenby RA, Brown JS, Maley CC (December 2013).
2993:
2908:
2891:
2364:
1476:
519:
Cytokine absorption leading to cytokine deprivation-mediated apoptosis
3889:
3594:
3489:
3398:
2413:
978:
detection and/or elimination by the host immune system. Induction of
873:
164:
129:
125:
121:
74:
3040:
2057:
1959:
1873:
1007:
103:
immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
3879:
3664:
3652:
3610:
3564:
3528:
2444:
921:
905:
889:
748:
740:
448:
444:
3432:
1040:
Pain, swelling, and disruption of tissue function by inflammation.
714:. After receiving an antigen these dendritic cells migrate to the
706:
The soluble antigens in the lumen of intestine are transported to
3884:
3698:
3547:
3518:
3324:
2178:
Clinica
Chimica Acta; International Journal of Clinical Chemistry
1566:
1223:
1113:
853:
701:
39:
3281:
2669:
Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (August 2007).
2668:
2579:
Mazzini E, Massimiliano L, Penna G, Rescigno M (February 2014).
2578:
2134:
2091:
1461:"Role of plasmacytoid dendritic cell subsets in allergic asthma"
151:
to avoid detection and destruction by the host's immune system.
3856:
3844:
3589:
3540:
2766:
1945:
1708:
Felton LD, Kauffmann G, Prescott B, Ottinger B (January 1955).
1707:
1567:
Becker JC, Andersen MH, Schrama D, Thor Straten P (July 2013).
933:
893:
881:
719:
552:
534:
485:
459:
398:
264:
241:
237:
229:
148:
106:
47:
1569:"Immune-suppressive properties of the tumor microenvironment"
789:
763:
426:
366:
110:
3114:
2717:
2137:"Regulatory T cells: how do they suppress immune responses?"
1624:
Murphy K (2012). "Chapter 1: Basic Concepts in Immunology".
1258:"The pathogenesis of systemic lupus erythematosus-an update"
758:
Another pathway of soluble antigen transport occurs through
1518:
1309:
805:
628:
548:
477:
473:
378:
2857:
Murphy K (2012). "Chapter 12: The Mucosal Immune System".
729:
159:
The phenomenon of immune tolerance was first described by
2807:
2529:
1043:
Tissue damage by inflammatory mediators (immunopathology)
924:, and high expression of tolerance-inducing ligands like
892:. Repeated administration of antibiotics, which can form
3168:
3022:
2039:
904:
Immune tolerance is an important means by which growing
65:
Immune tolerance is important for normal physiology and
2213:
562:
347:
from any of a variety of sources, including tolerizing
3169:
Medzhitov R, Schneider DS, Soares MP (February 2012).
2889:
2040:
Ganguly D, Haak S, Sisirak V, Reizis B (August 2013).
1859:
1458:
840:
2810:"Plasmacytoid dendritic cells mediate oral tolerance"
2619:
2175:
1059:
Neutralizes toxins and eliminates dangerous organisms
820:
1988:
1089:
Less selection pressure on pathogens for resistance
1076:
Direct damage by pathogen (toxins, digestion, etc.)
743:. The partially degraded antigens are presented on
3164:
3162:
3160:
1514:
1512:
1510:
1508:
1506:
1504:
1459:Maazi H, Lam J, Lombardi V, Akbari O (June 2013).
982:, for instance, has been noted in infections with
751:. The MHCII carrying vesicles are released on the
739:. The antigens are then partially degraded in the
631:(sFGL2), which suppresses the function of DCs and
2892:"Mechanisms of peripheral tolerance to allergens"
1310:Round JL, O'Connell RM, Mazmanian SK (May 2010).
1008:Tradeoffs between immune tolerance and resistance
335:(iTreg cells) in the peripheral tissue or nearby
3902:
3232:
1519:Curotto de Lafaille MA, Lafaille JJ (May 2009).
421:The involvement of T cells, later classified as
3228:
3226:
3224:
3222:
3157:
1903:
1901:
1899:
1810:
1501:
1218:
1216:
1214:
1212:
1210:
1208:
1206:
1204:
1177:
1175:
1173:
1171:
1169:
1167:
1165:
1049:Risk of autoimmunity, hypersensitivity, allergy
825:Oral tolerance is also established by inducing
735:antigens Dissolved antigens can be taken up by
355:, or in certain conditions surrounding tissue.
2941:"Allergen immunotherapy for allergic rhinitis"
2620:Laffont S, Siddiqui KR, Powrie F (July 2010).
2087:
2085:
1941:
1939:
1937:
1562:
1560:
1558:
1556:
1409:
702:Mechanisms of oral tolerance for food antigens
38:. It arises from prior exposure to a specific
16:State of unresponsiveness of the immune system
3475:
3367:
3233:Råberg L, Graham AL, Read AF (January 2009).
3025:"Life history trade-offs in cancer evolution"
2938:
2850:
2042:"The role of dendritic cells in autoimmunity"
1757:
1755:
1753:
1305:
1303:
1301:
899:
3438:International Conference on Immune Tolerance
3219:
2480:
2294:
2259:
1896:
1255:
1201:
1162:
2865:(8th ed.). Garland Sciences. pp.
2082:
1934:
1916:(8th ed.). Garland Sciences. pp.
1632:(8th ed.). Garland Sciences. pp.
1553:
747:after lysosome merging with MHCII carrying
3482:
3468:
2346:
1761:
1750:
1298:
1231:(8th ed.). Garland Science. pp.
1086:Reduced tissue damage from immune response
462:(reduced proliferation and IL-2 signaling)
303:) that can respond to self-antigens that:
3452:at the U.S. National Library of Medicine
3397:
3258:
3202:
3171:"Disease tolerance as a defense strategy"
3140:
3048:
2956:
2907:
2833:
2784:
2743:
2694:
2645:
2596:
2555:
2506:
2421:
2372:
2320:
2209:
2207:
2152:
2065:
1836:
1779:
1725:
1592:
1536:
1484:
1435:
1386:
1376:
1335:
1281:
1256:Choi J, Kim ST, Craft J (December 2012).
615:(HLA-G) that inhibits attack by maternal
551:costimulation, while iTreg cells require
314:, brain, or spinal cord not expressed by
272:
2979:
2255:
2253:
2216:Current Opinion in Organ Transplantation
1410:Verbsky JW, Chatila TA (December 2013).
1358:
1184:"Nobel Lecture: Immunological Tolerance"
964:
490:lymphocyte function-associated antigen 1
416:
198:
154:
99:autoimmune polyendocrine syndrome type 1
1365:Clinical & Developmental Immunology
1181:
730:Antigen presentation to dendritic cells
290:
3903:
3071:
2856:
2395:
2204:
1907:
1656:
1623:
1222:
567:
324:
3463:
2402:The Journal of Clinical Investigation
2342:
2340:
2250:
1079:Energy and resources lost to pathogen
782:
547:nTreg cells, when activated, require
343:produced upon T cell activation, and
2724:The Journal of Experimental Medicine
2675:The Journal of Experimental Medicine
2487:Clinical and Experimental Immunology
809:present in this environment secrete
591:
563:Tolerance in physiology and medicine
220:
124:, immune tolerance is vital for the
58:, taking place in other tissues and
841:Hypersensitivity and oral tolerance
393:(IDO) that depletes the amino acid
365:that make IL-10 but do not express
13:
2939:Petalas K, Durham SR (June 2013).
2337:
2262:Journal of Reproductive Immunology
1813:"The thymus and central tolerance"
1811:Sprent J, Kishimoto H (May 2001).
821:Other mechanisms of oral tolerance
14:
3922:
3426:
2481:Miron N, Cristea V (March 2012).
1130:Evolutionary medicine § tradeoffs
680:
647:
246:medullary thymic epithelial cells
136:response sufficiently to prevent
3339:10.1111/j.0105-2896.2006.00411.x
3296:10.1111/j.1600-065x.2006.00445.x
2982:Pediatric Allergy and Immunology
2499:10.1111/j.1365-2249.2011.04523.x
2349:"Oral tolerance to food protein"
2106:10.1046/j.1440-1711.2002.01068.x
1781:10.1097/00054725-200407000-00023
1762:Jump RL, Levine AD (July 2004).
1573:Cancer Immunology, Immunotherapy
946:myeloid derived suppressor cells
722:and induce differentiation into
718:. Here they interact with naïve
605:major histocompatibility complex
3361:
3318:
3275:
3108:
3065:
3016:
2973:
2932:
2883:
2801:
2760:
2711:
2662:
2613:
2572:
2523:
2474:
2438:
2389:
2295:Christiansen OB (August 2013).
2288:
2169:
2128:
2033:
1982:
1853:
1804:
1701:
1650:
1617:
1182:Medawar P (December 12, 1960).
691:its associated lymphoid tissues
389:also exists. Some DCs can make
3809:Immunoglobulin class switching
3074:British Journal of Haematology
2626:European Journal of Immunology
2347:Pabst O, Mowat AM (May 2012).
1452:
1403:
1352:
1249:
539:gut-associated lymphoid tissue
1:
2011:10.1016/j.febslet.2013.05.023
1416:Current Opinion in Pediatrics
1262:Current Opinion in Immunology
1155:
868:at mucosal surfaces suppress
642:Immune tolerance in pregnancy
635:involved in inflammation and
598:Immune tolerance in pregnancy
411:activation-induced cell death
2826:10.1016/j.immuni.2008.06.017
2786:10.1016/j.immuni.2011.01.016
2598:10.1016/j.immuni.2013.12.012
2460:10.1053/j.gastro.2007.02.043
2313:10.1016/j.molimm.2012.08.025
2228:10.1097/MOT.0b013e3283636fd5
1538:10.1016/j.immuni.2009.05.002
1428:10.1097/mop.0000000000000029
1150:Plant tolerance to herbivory
951:
835:plasmacytoid dendritic cells
87:systemic lupus erythematosus
7:
2094:Immunology and Cell Biology
1768:Inflammatory Bowel Diseases
1123:
1120:, and other such diseases.
667:inflammatory bowel diseases
619:. These cells also express
391:Indoleamine 2,3-dioxygenase
10:
3927:
3638:Polyclonal B cell response
2396:Weiner HL (October 2000).
2046:Nature Reviews. Immunology
1948:Nature Reviews. Immunology
1862:Nature Reviews. Immunology
1328:10.1016/j.jaut.2009.11.007
1118:inflammatory bowel disease
900:The tumor microenvironment
858:hypersensitivity reactions
629:fibrinogen-like proteins 2
595:
480:costimultory molecules on
185:Sir Frank McFarlane Burnet
115:inflammatory bowel disease
85:, with conditions such as
3872:
3830:
3772:
3673:
3603:
3511:
3504:
2297:"Reproductive immunology"
2274:10.1016/j.jri.2012.07.007
2190:10.1016/j.cca.2012.04.024
1585:10.1007/s00262-013-1434-6
1274:10.1016/j.coi.2012.10.004
3454:Medical Subject Headings
3433:Immune Tolerance Network
2141:International Immunology
1727:10.4049/jimmunol.74.1.17
1034:Elimination (resistance)
482:antigen presenting cells
458:after contact, inducing
353:antigen presenting cells
163:in 1945, who noted that
128:of genetically distinct
3390:10.1126/science.1148526
3195:10.1126/science.1214935
2861:Janeway's Immunobiology
1912:Janeway's Immunobiology
1628:Janeway's Immunobiology
1316:Journal of Autoimmunity
1227:Janeway's Immunobiology
1056:Reduces pathogen burden
870:type 2 CD4 helper cells
613:Human Leukocyte Antigen
611:cells express a unique
24:immunological tolerance
3752:Tolerance in pregnancy
3494:adaptive immune system
3251:10.1098/rstb.2008.0184
3029:Nature Reviews. Cancer
1829:10.1098/rstb.2001.0846
1679:10.1098/rspb.1983.0039
991:Listeria monocytogenes
970:
914:tumor microenvironment
716:mesenteric lymph nodes
484:upon interaction with
451:secretion upon contact
409:tissues can result in
250:thymic dendritic cells
132:, as it moderates the
3787:Somatic hypermutation
3621:Polyclonal antibodies
3616:Monoclonal antibodies
3327:Immunological Reviews
3284:Immunological Reviews
2638:10.1002/eji.200939957
2154:10.1093/intimm/dxp095
1714:Journal of Immunology
1092:Promotes commensalism
968:
417:nTreg vs. iTreg cells
199:Definitions and usage
155:Historical background
3804:Junctional diversity
3572:Antigen presentation
2736:10.1084/jem.20080039
2687:10.1084/jem.20070719
2301:Molecular Immunology
2184:(17–18): 1414–1418.
1140:Infectious tolerance
637:antigen presentation
312:islets of Langerhans
296:Peripheral tolerance
291:Peripheral tolerance
273:peripheral tolerance
91:rheumatoid arthritis
56:peripheral tolerance
3799:V(D)J recombination
3782:Affinity maturation
3534:Antigenic variation
3382:2007Sci...318..812R
3187:2012Sci...335..936M
2958:10.4193/Rhino12.086
2548:10.1038/nature10863
2003:2013FEBSL.587.2074V
1671:1983RSPSB.218..259F
1378:10.1155/2012/207403
1359:Perniola R (2012).
1062:Prevents parasitism
985:Helicobacter pylori
568:Allograft tolerance
499:Contact-independent
318:in thymic tissues).
145:pathogenic microbes
83:autoimmune diseases
46:, occurring in the
3443:2011-02-19 at the
2353:Mucosal Immunology
980:regulatory T cells
971:
783:Regulatory T cells
724:regulatory T cells
675:ulcerative colitis
472:Downregulation of
437:Contact-dependent:
269:regulatory T cells
120:In the context of
3898:
3897:
3826:
3825:
3576:professional APCs
3376:(5851): 812–814.
3181:(6071): 936–941.
3133:10.1111/imm.12036
3086:10.1111/bjh.12380
2994:10.1111/pai.12001
2909:10.1111/all.12085
2876:978-0-8153-4243-4
2730:(11): 2483–2490.
2542:(7389): 345–349.
2365:10.1038/mi.2012.4
2147:(10): 1105–1111.
1997:(13): 2074–2078.
1927:978-0-8153-4243-4
1823:(1409): 609–616.
1665:(1212): 259–285.
1643:978-0-8153-4243-4
1477:10.1111/all.12166
1242:978-0-8153-4243-4
1101:
1100:
1095:Lower energy cost
886:atopic dermatitis
592:Fetal development
465:Interaction with
407:immune privileged
325:central tolerance
283:process detailed
254:bone marrow cells
226:Central tolerance
221:Central tolerance
210:immunosuppression
44:central tolerance
3918:
3792:Clonal selection
3764:Immune privilege
3759:Immunodeficiency
3714:Cross-reactivity
3704:Hypersensitivity
3509:
3508:
3484:
3477:
3470:
3461:
3460:
3450:Immune+tolerance
3420:
3419:
3401:
3365:
3359:
3358:
3322:
3316:
3315:
3279:
3273:
3272:
3262:
3230:
3217:
3216:
3206:
3166:
3155:
3154:
3144:
3112:
3106:
3105:
3069:
3063:
3062:
3052:
3020:
3014:
3013:
2977:
2971:
2970:
2960:
2936:
2930:
2929:
2911:
2887:
2881:
2880:
2864:
2854:
2848:
2847:
2837:
2805:
2799:
2798:
2788:
2764:
2758:
2757:
2747:
2715:
2709:
2708:
2698:
2681:(8): 1765–1774.
2666:
2660:
2659:
2649:
2632:(7): 1877–1883.
2617:
2611:
2610:
2600:
2576:
2570:
2569:
2559:
2527:
2521:
2520:
2510:
2478:
2472:
2471:
2454:(5): 1866–1876.
2448:Gastroenterology
2442:
2436:
2435:
2425:
2414:10.1172/jci11348
2393:
2387:
2386:
2376:
2344:
2335:
2334:
2324:
2292:
2286:
2285:
2257:
2248:
2247:
2211:
2202:
2201:
2173:
2167:
2166:
2156:
2132:
2126:
2125:
2089:
2080:
2079:
2069:
2037:
2031:
2030:
1986:
1980:
1979:
1943:
1932:
1931:
1915:
1905:
1894:
1893:
1857:
1851:
1850:
1840:
1808:
1802:
1801:
1783:
1759:
1748:
1747:
1729:
1705:
1699:
1698:
1654:
1648:
1647:
1631:
1621:
1615:
1614:
1596:
1579:(7): 1137–1148.
1564:
1551:
1550:
1540:
1516:
1499:
1498:
1488:
1456:
1450:
1449:
1439:
1407:
1401:
1400:
1390:
1380:
1356:
1350:
1349:
1339:
1322:(3): J220–J225.
1307:
1296:
1295:
1285:
1253:
1247:
1246:
1230:
1220:
1199:
1198:
1196:
1194:
1179:
1046:High energy cost
1020:
1019:
847:hypersensitivity
454:Upregulation of
30:, refers to the
22:, also known as
20:Immune tolerance
3926:
3925:
3921:
3920:
3919:
3917:
3916:
3915:
3901:
3900:
3899:
3894:
3868:
3822:
3768:
3747:Clonal deletion
3675:
3669:
3599:
3500:
3488:
3445:Wayback Machine
3429:
3424:
3423:
3366:
3362:
3323:
3319:
3280:
3276:
3245:(1513): 37–49.
3231:
3220:
3167:
3158:
3113:
3109:
3070:
3066:
3041:10.1038/nrc3606
3035:(12): 883–892.
3021:
3017:
2978:
2974:
2937:
2933:
2888:
2884:
2877:
2855:
2851:
2806:
2802:
2765:
2761:
2716:
2712:
2667:
2663:
2618:
2614:
2577:
2573:
2528:
2524:
2479:
2475:
2443:
2439:
2394:
2390:
2345:
2338:
2293:
2289:
2258:
2251:
2212:
2205:
2174:
2170:
2133:
2129:
2090:
2083:
2058:10.1038/nri3477
2038:
2034:
1987:
1983:
1960:10.1038/nri2785
1944:
1935:
1928:
1906:
1897:
1874:10.1038/nri1707
1868:(10): 772–782.
1858:
1854:
1809:
1805:
1760:
1751:
1706:
1702:
1655:
1651:
1644:
1622:
1618:
1565:
1554:
1517:
1502:
1457:
1453:
1408:
1404:
1357:
1353:
1308:
1299:
1254:
1250:
1243:
1221:
1202:
1192:
1190:
1188:The Nobel Prize
1180:
1163:
1158:
1126:
1010:
954:
902:
843:
823:
785:
732:
708:dendritic cells
704:
695:intestinal wall
683:
671:Crohn's disease
650:
600:
594:
586:gene signatures
570:
565:
419:
349:dendritic cells
337:lymphoid tissue
293:
223:
201:
193:clonal deletion
157:
95:type 1 diabetes
36:immune response
28:immunotolerance
17:
12:
11:
5:
3924:
3914:
3913:
3896:
3895:
3893:
3892:
3887:
3882:
3876:
3874:
3870:
3869:
3867:
3866:
3861:
3860:
3859:
3849:
3848:
3847:
3836:
3834:
3828:
3827:
3824:
3823:
3821:
3820:
3811:
3806:
3801:
3796:
3795:
3794:
3789:
3778:
3776:
3774:Immunogenetics
3770:
3769:
3767:
3766:
3761:
3756:
3755:
3754:
3749:
3744:
3739:
3734:
3722:
3721:
3719:Co-stimulation
3716:
3711:
3706:
3701:
3696:
3691:
3686:
3679:
3677:
3671:
3670:
3668:
3667:
3662:
3660:Immune complex
3656:
3655:
3650:
3645:
3640:
3635:
3634:
3633:
3628:
3623:
3618:
3607:
3605:
3601:
3600:
3598:
3597:
3592:
3587:
3582:
3580:Dendritic cell
3568:
3567:
3562:
3561:
3560:
3558:Conformational
3555:
3544:
3543:
3538:
3537:
3536:
3531:
3526:
3515:
3513:
3506:
3502:
3501:
3487:
3486:
3479:
3472:
3464:
3458:
3457:
3447:
3435:
3428:
3427:External links
3425:
3422:
3421:
3360:
3317:
3274:
3218:
3156:
3127:(2): 105–115.
3107:
3080:(3): 313–325.
3064:
3015:
2972:
2931:
2902:(2): 161–170.
2882:
2875:
2849:
2820:(3): 464–475.
2800:
2779:(2): 237–246.
2759:
2710:
2661:
2612:
2591:(2): 248–261.
2571:
2522:
2493:(3): 405–412.
2473:
2437:
2408:(8): 935–937.
2388:
2359:(3): 232–239.
2336:
2287:
2249:
2222:(4): 416–420.
2203:
2168:
2127:
2100:(2): 131–137.
2081:
2052:(8): 566–577.
2032:
1981:
1954:(7): 490–500.
1933:
1926:
1895:
1852:
1803:
1774:(4): 462–478.
1749:
1700:
1649:
1642:
1616:
1552:
1531:(5): 626–635.
1500:
1471:(6): 695–701.
1451:
1422:(6): 708–714.
1402:
1351:
1297:
1268:(6): 651–657.
1248:
1241:
1200:
1160:
1159:
1157:
1154:
1153:
1152:
1147:
1142:
1137:
1132:
1125:
1122:
1099:
1098:
1097:
1096:
1093:
1090:
1087:
1082:
1081:
1080:
1077:
1072:
1066:
1065:
1064:
1063:
1060:
1057:
1052:
1051:
1050:
1047:
1044:
1041:
1036:
1030:
1029:
1026:
1023:
1009:
1006:
953:
950:
901:
898:
842:
839:
822:
819:
784:
781:
731:
728:
712:lamina propria
703:
700:
682:
681:Oral tolerance
679:
649:
648:The microbiome
646:
596:Main article:
593:
590:
569:
566:
564:
561:
560:
559:
556:
555:costimulation.
545:
542:
523:
522:
521:
520:
517:
511:
501:
500:
496:
495:
494:
493:
470:
463:
452:
439:
438:
418:
415:
405:expression by
320:
319:
308:
292:
289:
222:
219:
200:
197:
181:
180:
156:
153:
79:gut microbiota
15:
9:
6:
4:
3:
2:
3923:
3912:
3909:
3908:
3906:
3891:
3888:
3886:
3883:
3881:
3878:
3877:
3875:
3871:
3865:
3862:
3858:
3855:
3854:
3853:
3850:
3846:
3843:
3842:
3841:
3838:
3837:
3835:
3833:
3829:
3819:
3815:
3812:
3810:
3807:
3805:
3802:
3800:
3797:
3793:
3790:
3788:
3785:
3784:
3783:
3780:
3779:
3777:
3775:
3771:
3765:
3762:
3760:
3757:
3753:
3750:
3748:
3745:
3743:
3742:Clonal anergy
3740:
3738:
3735:
3733:
3730:
3729:
3728:
3724:
3723:
3720:
3717:
3715:
3712:
3710:
3707:
3705:
3702:
3700:
3697:
3695:
3692:
3690:
3687:
3685:
3681:
3680:
3678:
3672:
3666:
3663:
3661:
3658:
3657:
3654:
3651:
3649:
3646:
3644:
3641:
3639:
3636:
3632:
3631:Microantibody
3629:
3627:
3624:
3622:
3619:
3617:
3614:
3613:
3612:
3609:
3608:
3606:
3602:
3596:
3593:
3591:
3588:
3586:
3583:
3581:
3577:
3573:
3570:
3569:
3566:
3563:
3559:
3556:
3554:
3551:
3550:
3549:
3546:
3545:
3542:
3539:
3535:
3532:
3530:
3527:
3525:
3522:
3521:
3520:
3517:
3516:
3514:
3510:
3507:
3503:
3499:
3495:
3492:
3485:
3480:
3478:
3473:
3471:
3466:
3465:
3462:
3455:
3451:
3448:
3446:
3442:
3439:
3436:
3434:
3431:
3430:
3417:
3413:
3409:
3405:
3400:
3395:
3391:
3387:
3383:
3379:
3375:
3371:
3364:
3356:
3352:
3348:
3344:
3340:
3336:
3332:
3328:
3321:
3313:
3309:
3305:
3301:
3297:
3293:
3289:
3285:
3278:
3270:
3266:
3261:
3256:
3252:
3248:
3244:
3240:
3236:
3229:
3227:
3225:
3223:
3214:
3210:
3205:
3200:
3196:
3192:
3188:
3184:
3180:
3176:
3172:
3165:
3163:
3161:
3152:
3148:
3143:
3138:
3134:
3130:
3126:
3122:
3118:
3111:
3103:
3099:
3095:
3091:
3087:
3083:
3079:
3075:
3068:
3060:
3056:
3051:
3046:
3042:
3038:
3034:
3030:
3026:
3019:
3011:
3007:
3003:
2999:
2995:
2991:
2987:
2983:
2976:
2968:
2964:
2959:
2954:
2951:(2): 99–110.
2950:
2946:
2942:
2935:
2927:
2923:
2919:
2915:
2910:
2905:
2901:
2897:
2893:
2886:
2878:
2872:
2868:
2863:
2862:
2853:
2845:
2841:
2836:
2831:
2827:
2823:
2819:
2815:
2811:
2804:
2796:
2792:
2787:
2782:
2778:
2774:
2770:
2763:
2755:
2751:
2746:
2741:
2737:
2733:
2729:
2725:
2721:
2714:
2706:
2702:
2697:
2692:
2688:
2684:
2680:
2676:
2672:
2665:
2657:
2653:
2648:
2643:
2639:
2635:
2631:
2627:
2623:
2616:
2608:
2604:
2599:
2594:
2590:
2586:
2582:
2575:
2567:
2563:
2558:
2553:
2549:
2545:
2541:
2537:
2533:
2526:
2518:
2514:
2509:
2504:
2500:
2496:
2492:
2488:
2484:
2477:
2469:
2465:
2461:
2457:
2453:
2449:
2441:
2433:
2429:
2424:
2419:
2415:
2411:
2407:
2403:
2399:
2392:
2384:
2380:
2375:
2370:
2366:
2362:
2358:
2354:
2350:
2343:
2341:
2332:
2328:
2323:
2318:
2314:
2310:
2306:
2302:
2298:
2291:
2283:
2279:
2275:
2271:
2267:
2263:
2256:
2254:
2245:
2241:
2237:
2233:
2229:
2225:
2221:
2217:
2210:
2208:
2199:
2195:
2191:
2187:
2183:
2179:
2172:
2164:
2160:
2155:
2150:
2146:
2142:
2138:
2131:
2123:
2119:
2115:
2111:
2107:
2103:
2099:
2095:
2088:
2086:
2077:
2073:
2068:
2063:
2059:
2055:
2051:
2047:
2043:
2036:
2028:
2024:
2020:
2016:
2012:
2008:
2004:
2000:
1996:
1992:
1985:
1977:
1973:
1969:
1965:
1961:
1957:
1953:
1949:
1942:
1940:
1938:
1929:
1923:
1919:
1914:
1913:
1904:
1902:
1900:
1891:
1887:
1883:
1879:
1875:
1871:
1867:
1863:
1856:
1848:
1844:
1839:
1834:
1830:
1826:
1822:
1818:
1814:
1807:
1799:
1795:
1791:
1787:
1782:
1777:
1773:
1769:
1765:
1758:
1756:
1754:
1745:
1741:
1737:
1733:
1728:
1723:
1719:
1715:
1711:
1704:
1696:
1692:
1688:
1684:
1680:
1676:
1672:
1668:
1664:
1660:
1653:
1645:
1639:
1635:
1630:
1629:
1620:
1612:
1608:
1604:
1600:
1595:
1590:
1586:
1582:
1578:
1574:
1570:
1563:
1561:
1559:
1557:
1548:
1544:
1539:
1534:
1530:
1526:
1522:
1515:
1513:
1511:
1509:
1507:
1505:
1496:
1492:
1487:
1482:
1478:
1474:
1470:
1466:
1462:
1455:
1447:
1443:
1438:
1433:
1429:
1425:
1421:
1417:
1413:
1406:
1398:
1394:
1389:
1384:
1379:
1374:
1370:
1366:
1362:
1355:
1347:
1343:
1338:
1333:
1329:
1325:
1321:
1317:
1313:
1306:
1304:
1302:
1293:
1289:
1284:
1279:
1275:
1271:
1267:
1263:
1259:
1252:
1244:
1238:
1234:
1229:
1228:
1219:
1217:
1215:
1213:
1211:
1209:
1207:
1205:
1189:
1185:
1178:
1176:
1174:
1172:
1170:
1168:
1166:
1161:
1151:
1148:
1146:
1143:
1141:
1138:
1136:
1135:Immunotherapy
1133:
1131:
1128:
1127:
1121:
1119:
1115:
1111:
1105:
1094:
1091:
1088:
1085:
1084:
1083:
1078:
1075:
1074:
1073:
1071:
1068:
1067:
1061:
1058:
1055:
1054:
1053:
1048:
1045:
1042:
1039:
1038:
1037:
1035:
1032:
1031:
1027:
1024:
1022:
1021:
1018:
1014:
1005:
1003:
999:
998:
997:Brugia malayi
993:
992:
987:
986:
981:
975:
967:
963:
960:
959:reaction norm
949:
947:
943:
939:
935:
931:
927:
923:
919:
915:
911:
910:stromal cells
907:
897:
895:
891:
887:
883:
879:
875:
871:
867:
863:
859:
855:
851:
848:
838:
836:
832:
828:
818:
814:
812:
807:
803:
802:retinoic acid
799:
795:
791:
780:
778:
777:gap junctions
774:
771:
767:
765:
761:
756:
754:
750:
746:
742:
738:
727:
725:
721:
717:
713:
709:
699:
696:
692:
688:
678:
676:
672:
668:
663:
662:retinoic acid
659:
655:
645:
643:
638:
634:
630:
626:
622:
618:
614:
610:
606:
599:
589:
587:
583:
579:
575:
557:
554:
550:
546:
543:
540:
536:
532:
528:
527:
526:
518:
516:
513:Secretion of
512:
509:
506:Secretion of
505:
504:
503:
502:
498:
497:
491:
487:
483:
479:
475:
471:
468:
464:
461:
457:
453:
450:
446:
443:
442:
441:
440:
436:
435:
434:
430:
428:
424:
414:
412:
408:
404:
400:
396:
392:
388:
384:
380:
376:
372:
368:
364:
360:
356:
354:
351:(DCs), other
350:
346:
342:
338:
334:
328:
326:
317:
313:
309:
306:
305:
304:
302:
297:
288:
286:
280:
276:
274:
270:
266:
261:
259:
255:
251:
247:
243:
242:B lymphocytes
239:
235:
231:
227:
218:
214:
211:
205:
196:
194:
190:
186:
179:
176:
175:
174:
171:
170:Peter Medawar
166:
162:
152:
150:
146:
141:
139:
135:
131:
127:
123:
118:
116:
112:
108:
104:
101:(APS-1), and
100:
96:
92:
88:
84:
80:
76:
72:
68:
63:
61:
57:
53:
49:
45:
41:
37:
33:
32:immune system
29:
25:
21:
3726:
3709:Inflammation
3694:Alloimmunity
3689:Autoimmunity
3674:Immunity vs.
3626:Autoantibody
3524:Superantigen
3373:
3369:
3363:
3330:
3326:
3320:
3287:
3283:
3277:
3242:
3238:
3178:
3174:
3124:
3120:
3110:
3077:
3073:
3067:
3032:
3028:
3018:
2985:
2981:
2975:
2948:
2944:
2934:
2899:
2895:
2885:
2860:
2852:
2817:
2813:
2803:
2776:
2772:
2762:
2727:
2723:
2713:
2678:
2674:
2664:
2629:
2625:
2615:
2588:
2584:
2574:
2539:
2535:
2525:
2490:
2486:
2476:
2451:
2447:
2440:
2405:
2401:
2391:
2356:
2352:
2304:
2300:
2290:
2268:(1–2): 1–7.
2265:
2261:
2219:
2215:
2181:
2177:
2171:
2144:
2140:
2130:
2097:
2093:
2049:
2045:
2035:
1994:
1991:FEBS Letters
1990:
1984:
1951:
1947:
1911:
1865:
1861:
1855:
1820:
1816:
1806:
1771:
1767:
1720:(1): 17–26.
1717:
1713:
1703:
1662:
1658:
1652:
1627:
1619:
1576:
1572:
1528:
1524:
1468:
1464:
1454:
1419:
1415:
1405:
1368:
1364:
1354:
1319:
1315:
1265:
1261:
1251:
1226:
1191:. Retrieved
1187:
1145:Mithridatism
1110:autoimmunity
1106:
1102:
1069:
1033:
1015:
1011:
995:
989:
983:
976:
972:
955:
903:
852:
844:
824:
815:
786:
768:
760:goblet cells
757:
733:
705:
684:
651:
601:
571:
524:
431:
420:
413:of T cells.
357:
329:
321:
294:
281:
277:
262:
224:
215:
206:
202:
189:Frank Fenner
182:
177:
158:
142:
119:
71:autoimmunity
64:
27:
23:
19:
18:
3832:Lymphocytes
3491:Lymphocytic
3333:: 163–169.
3290:: 229–238.
2307:(1): 8–15.
878:eosinophils
864:, TR1, and
831:portal vein
773:macrophages
753:basolateral
737:enterocytes
633:macrophages
609:trophoblast
531:lymph nodes
373:-secreting
234:bone marrow
161:Ray D. Owen
138:miscarriage
67:homeostasis
60:lymph nodes
52:bone marrow
3911:Immunology
3873:Substances
3737:Peripheral
3725:Inaction:
3604:Antibodies
3585:Macrophage
3498:complement
3121:Immunology
2988:(1): 3–9.
1371:: 207403.
1156:References
874:mast cells
862:Treg cells
654:microbiome
574:allografts
469:on T cells
423:Treg cells
395:tryptophan
359:Treg cells
333:Treg cells
134:alloimmune
3890:Cytolysin
3880:Cytokines
3727:Tolerance
3676:tolerance
3595:Immunogen
3399:1842/2140
2945:Rhinology
2244:205838923
1070:Tolerance
1028:Benefits
952:Evolution
866:Th3 cells
794:Th1 cells
749:endosomes
741:lysosomes
363:TR1 cells
165:dizygotic
130:offspring
126:gestation
122:pregnancy
75:allergens
3905:Category
3840:Cellular
3684:Immunity
3682:Action:
3665:Paratope
3653:Idiotype
3643:Allotype
3611:Antibody
3565:Mimotope
3529:Allergen
3512:Antigens
3505:Lymphoid
3441:Archived
3416:16697260
3408:17975068
3355:19863894
3347:16903913
3312:37377768
3304:17100888
3269:18926971
3213:22363001
3151:23216602
3094:23691926
3059:24213474
3010:27655449
3002:22963144
2967:23671890
2926:24008758
2918:23253293
2844:18789731
2814:Immunity
2795:21333554
2773:Immunity
2754:18852290
2705:17620363
2656:20432234
2607:24462723
2585:Immunity
2566:22422267
2517:22288583
2468:17484880
2432:11032852
2383:22318493
2331:23062611
2282:23021867
2236:23838646
2198:22580152
2163:19737784
2122:13419948
2114:11940113
2076:23827956
2027:23330772
2019:23707422
1976:10861133
1968:20559327
1882:16200080
1847:11375064
1790:15475760
1744:33224134
1736:13233513
1695:20599562
1611:20996186
1603:23666510
1594:11029603
1547:19464985
1525:Immunity
1495:23662841
1446:24240290
1397:23125865
1346:19963349
1292:23131610
1124:See also
1002:NK cells
942:exosomes
922:arginase
890:rhinitis
617:NK cells
582:γδT cell
449:perforin
445:Granzyme
327:above).
275:below).
3885:Opsonin
3864:NK cell
3852:Humoral
3732:Central
3699:Allergy
3648:Isotype
3548:Epitope
3519:Antigen
3378:Bibcode
3370:Science
3260:2666700
3204:3564547
3183:Bibcode
3175:Science
3142:3575763
3102:9062219
3050:4010142
2896:Allergy
2835:3545652
2745:2571923
2696:2118687
2647:6108414
2557:3313460
2508:3374272
2374:3328017
2322:1383872
2067:4160805
1999:Bibcode
1838:1088448
1798:5751200
1687:6136042
1667:Bibcode
1486:3693732
1465:Allergy
1437:4047515
1388:3485510
1337:3155383
1283:3508331
1193:24 July
1114:allergy
894:haptens
854:Allergy
770:CX3CR1+
720:T cells
710:in the
578:NK cell
541:(GALT).
492:(LFA-1)
149:cancers
40:antigen
3857:B cell
3845:T cell
3590:B cell
3553:Linear
3541:Hapten
3456:(MeSH)
3414:
3406:
3353:
3345:
3310:
3302:
3267:
3257:
3211:
3201:
3149:
3139:
3100:
3092:
3057:
3047:
3008:
3000:
2965:
2924:
2916:
2873:
2869:–502.
2842:
2832:
2793:
2752:
2742:
2703:
2693:
2654:
2644:
2605:
2564:
2554:
2536:Nature
2515:
2505:
2466:
2430:
2423:314352
2420:
2381:
2371:
2329:
2319:
2280:
2242:
2234:
2196:
2161:
2120:
2112:
2074:
2064:
2025:
2017:
1974:
1966:
1924:
1920:–334.
1890:563786
1888:
1880:
1845:
1835:
1796:
1788:
1742:
1734:
1693:
1685:
1640:
1609:
1601:
1591:
1545:
1493:
1483:
1444:
1434:
1395:
1385:
1344:
1334:
1290:
1280:
1239:
1235:–668.
936:, and
934:CTLA-4
906:tumors
882:asthma
876:, and
827:anergy
790:Foxp3+
764:CD103+
687:mucosa
553:CTLA-4
537:, and
535:spleen
486:CTLA-4
460:anergy
399:anergy
265:anergy
230:thymus
113:, and
107:asthma
48:thymus
3412:S2CID
3351:S2CID
3308:S2CID
3098:S2CID
3006:S2CID
2922:S2CID
2240:S2CID
2118:S2CID
2023:S2CID
1972:S2CID
1886:S2CID
1794:S2CID
1740:S2CID
1691:S2CID
1636:–15.
1607:S2CID
1025:Costs
811:IL-10
745:MHCII
669:like
658:TGF-β
515:IL-10
508:TGF-β
427:Foxp3
387:TGF-β
383:IL-10
371:TGF-β
367:Foxp3
345:TGF-β
252:, or
111:atopy
54:, or
3496:and
3404:PMID
3343:PMID
3300:PMID
3265:PMID
3209:PMID
3147:PMID
3090:PMID
3055:PMID
2998:PMID
2963:PMID
2914:PMID
2871:ISBN
2840:PMID
2791:PMID
2750:PMID
2701:PMID
2652:PMID
2603:PMID
2562:PMID
2513:PMID
2464:PMID
2428:PMID
2379:PMID
2327:PMID
2278:PMID
2232:PMID
2194:PMID
2159:PMID
2110:PMID
2072:PMID
2015:PMID
1964:PMID
1922:ISBN
1878:PMID
1843:PMID
1786:PMID
1732:PMID
1683:PMID
1638:ISBN
1599:PMID
1543:PMID
1491:PMID
1442:PMID
1393:PMID
1369:2012
1342:PMID
1288:PMID
1237:ISBN
1195:2020
930:PD-1
926:FasL
920:and
884:and
856:and
806:CCR9
800:and
798:TGFβ
689:and
673:and
660:and
580:and
549:CD28
478:CD86
474:CD80
456:cAMP
403:FasL
385:and
379:CD22
341:IL-2
316:AIRE
301:TCRs
285:here
258:AIRE
248:and
240:and
236:for
232:and
187:and
77:and
50:and
3818:HLA
3814:MHC
3394:hdl
3386:doi
3374:318
3335:doi
3331:212
3292:doi
3288:214
3255:PMC
3247:doi
3243:364
3199:PMC
3191:doi
3179:335
3137:PMC
3129:doi
3125:138
3082:doi
3078:162
3045:PMC
3037:doi
2990:doi
2953:doi
2904:doi
2867:465
2830:PMC
2822:doi
2781:doi
2740:PMC
2732:doi
2728:205
2691:PMC
2683:doi
2679:204
2642:PMC
2634:doi
2593:doi
2552:PMC
2544:doi
2540:483
2503:PMC
2495:doi
2491:167
2456:doi
2452:132
2418:PMC
2410:doi
2406:106
2369:PMC
2361:doi
2317:PMC
2309:doi
2270:doi
2224:doi
2186:doi
2182:413
2149:doi
2102:doi
2062:PMC
2054:doi
2007:doi
1995:587
1956:doi
1918:275
1870:doi
1833:PMC
1825:doi
1821:356
1776:doi
1722:doi
1675:doi
1663:218
1589:PMC
1581:doi
1533:doi
1481:PMC
1473:doi
1432:PMC
1424:doi
1383:PMC
1373:doi
1332:PMC
1324:doi
1278:PMC
1270:doi
1233:611
918:IDO
644:).
625:DCs
621:IDO
488:or
447:or
375:TH3
26:or
3907::
3578::
3410:.
3402:.
3392:.
3384:.
3372:.
3349:.
3341:.
3329:.
3306:.
3298:.
3286:.
3263:.
3253:.
3241:.
3237:.
3221:^
3207:.
3197:.
3189:.
3177:.
3173:.
3159:^
3145:.
3135:.
3123:.
3119:.
3096:.
3088:.
3076:.
3053:.
3043:.
3033:13
3031:.
3027:.
3004:.
2996:.
2986:24
2984:.
2961:.
2949:51
2947:.
2943:.
2920:.
2912:.
2900:68
2898:.
2894:.
2838:.
2828:.
2818:29
2816:.
2812:.
2789:.
2777:34
2775:.
2771:.
2748:.
2738:.
2726:.
2722:.
2699:.
2689:.
2677:.
2673:.
2650:.
2640:.
2630:40
2628:.
2624:.
2601:.
2589:40
2587:.
2583:.
2560:.
2550:.
2538:.
2534:.
2511:.
2501:.
2489:.
2485:.
2462:.
2450:.
2426:.
2416:.
2404:.
2400:.
2377:.
2367:.
2355:.
2351:.
2339:^
2325:.
2315:.
2305:55
2303:.
2299:.
2276:.
2266:96
2264:.
2252:^
2238:.
2230:.
2220:18
2218:.
2206:^
2192:.
2180:.
2157:.
2145:21
2143:.
2139:.
2116:.
2108:.
2098:80
2096:.
2084:^
2070:.
2060:.
2050:13
2048:.
2044:.
2021:.
2013:.
2005:.
1993:.
1970:.
1962:.
1952:10
1950:.
1936:^
1898:^
1884:.
1876:.
1864:.
1841:.
1831:.
1819:.
1815:.
1792:.
1784:.
1772:10
1770:.
1766:.
1752:^
1738:.
1730:.
1718:74
1716:.
1712:.
1689:.
1681:.
1673:.
1661:.
1634:13
1605:.
1597:.
1587:.
1577:62
1575:.
1571:.
1555:^
1541:.
1529:30
1527:.
1523:.
1503:^
1489:.
1479:.
1469:68
1467:.
1463:.
1440:.
1430:.
1420:25
1418:.
1414:.
1391:.
1381:.
1367:.
1363:.
1340:.
1330:.
1320:34
1318:.
1314:.
1300:^
1286:.
1276:.
1266:24
1264:.
1260:.
1203:^
1186:.
1164:^
1116:,
1112:,
994:,
988:,
938:B7
932:,
928:,
872:,
677:.
533:,
467:B7
369:,
260:.
140:.
117:.
109:,
97:,
93:,
89:,
3816:/
3574:/
3483:e
3476:t
3469:v
3418:.
3396::
3388::
3380::
3357:.
3337::
3314:.
3294::
3271:.
3249::
3215:.
3193::
3185::
3153:.
3131::
3104:.
3084::
3061:.
3039::
3012:.
2992::
2969:.
2955::
2928:.
2906::
2879:.
2846:.
2824::
2797:.
2783::
2756:.
2734::
2707:.
2685::
2658:.
2636::
2609:.
2595::
2568:.
2546::
2519:.
2497::
2470:.
2458::
2434:.
2412::
2385:.
2363::
2357:5
2333:.
2311::
2284:.
2272::
2246:.
2226::
2200:.
2188::
2165:.
2151::
2124:.
2104::
2078:.
2056::
2029:.
2009::
2001::
1978:.
1958::
1930:.
1892:.
1872::
1866:5
1849:.
1827::
1800:.
1778::
1746:.
1724::
1697:.
1677::
1669::
1646:.
1613:.
1583::
1549:.
1535::
1497:.
1475::
1448:.
1426::
1399:.
1375::
1348:.
1326::
1294:.
1272::
1245:.
1197:.
476:/
238:T
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.