'''Infectious tolerance''' is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural ''in vivo'' process.<ref>{{Cite journal|last1=Cobbold|first1=S.|last2=Waldmann|first2=H.|date=October 1998|title=Infectious tolerance|journal=Current Opinion in Immunology|volume=10|issue=5|pages=518–524|issn=0952-7915|pmid=9794831|doi=10.1016/S0952-7915(98)80217-3}}</ref> A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy.<ref>{{Cite journal|last1=Kendal|first1=Adrian R.|last2=Waldmann|first2=Herman|date=October 2010|title=Infectious tolerance: therapeutic potential|journal=Current Opinion in Immunology|volume=22|issue=5|pages=560–565|doi=10.1016/j.coi.2010.08.002|issn=1879-0372|pmid=20829013}}</ref>
== History == The term "infectious tolerance" was originally used by Gershon and Kondo in 1970<ref>{{Cite journal|last1=Gershon|first1=R. K.|last2=Kondo|first2=K.|date=December 1971|title=Infectious immunological tolerance|journal=Immunology|volume=21|issue=6|pages=903–914|issn=0019-2805|pmc=1408252|pmid=4943147}}</ref> for suppression of naive lymphocyte populations by cells with regulatory function and for the ability to transfer a state of unresponsiveness from one animal to another.<ref>{{Cite journal|last=Gershon|first=R. K.|date=1975|title=A disquisition on suppressor T cells|journal=Transplantation Reviews|volume=26|pages=170–185|issn=0082-5948|pmid=1101469|doi=10.1111/j.1600-065x.1975.tb00179.x|s2cid=39375586}}</ref> Gershon and Kondo discovered that T cells can not only amplify but also diminish immune responses.<ref>{{Cite journal|last1=Gershon|first1=R. K.|last2=Kondo|first2=K.|date=May 1970|title=Cell interactions in the induction of tolerance: the role of thymic lymphocytes|journal=Immunology|volume=18|issue=5|pages=723–737|issn=0019-2805|pmc=1455602|pmid=4911896}}</ref> The T cell population causing this down-regulation was called suppressor T cells and was intensively studied for the following years (nowadays they are called regulatory T cells and are again a very attractive for research).<ref>{{Cite journal|last1=Sakaguchi|first1=Shimon|last2=Wing|first2=Kajsa|last3=Miyara|first3=Makoto|date=November 2007|title=Regulatory T cells - a brief history and perspective|journal=European Journal of Immunology|volume=37|issue=Suppl 1 |pages=S116–123|doi=10.1002/eji.200737593|issn=0014-2980|pmid=17972355|doi-access=free}}</ref> These and other research in the 1970s showed greater complexity of immune regulation, unfortunately these experiments were largely disregarded, as methodological difficulties prevented clear evidence. Later developed new tolerogenic strategies have provided strong evidence to re-evaluate the phenomenon of T cell mediated suppression, in particular the use of non-depleting anti-CD4 monoclonal antibodies, demonstrating that neither thymus nor clonal deletion is necessary to induce tolerance.<ref>{{Cite journal|last1=Qin|first1=S. X.|last2=Wise|first2=M.|last3=Cobbold|first3=S. P.|last4=Leong|first4=L.|last5=Kong|first5=Y. C.|last6=Parnes|first6=J. R.|last7=Waldmann|first7=H.|date=December 1990|title=Induction of tolerance in peripheral T cells with monoclonal antibodies|journal=European Journal of Immunology|volume=20|issue=12|pages=2737–2745|doi=10.1002/eji.1830201231|issn=0014-2980|pmid=1702726|s2cid=30354546}}</ref> In 1989 was successfully induced classical transplantation tolerance to skin grafts in adult mice using antibodies blocking T cell coreceptors in CD4+ populations.<ref>{{Cite journal|last1=Qin|first1=S. X.|last2=Cobbold|first2=S.|last3=Benjamin|first3=R.|last4=Waldmann|first4=H.|date=1989-03-01|title=Induction of classical transplantation tolerance in the adult|journal=The Journal of Experimental Medicine|volume=169|issue=3|pages=779–794|issn=0022-1007|pmc=2189271|pmid=2647894|doi=10.1084/jem.169.3.779}}</ref> Later was shown that the effect of monoclonal antibodies is formation of regulatory T lymphocytes.<ref>{{Cite journal|last1=Tilney|first1=N. L.|last2=Guttmann|first2=R. D.|date=1997-10-15|title=Effects of initial ischemia/reperfusion injury on the transplanted kidney|journal=Transplantation|volume=64|issue=7|pages=945–947|issn=0041-1337|pmid=9381538|doi=10.1097/00007890-199710150-00001|doi-access=free}}</ref> It has been shown that transfer of tolerance to other recipients can be made without further manipulation and that this tolerance transfer depends only on CD4+ T-lymphocytes.<ref>{{Cite journal|last=Kahan|first=B. D.|date=December 1993|title=Toward a rational design of clinical trials of immunosuppressive agents in transplantation|journal=Immunological Reviews|volume=136|pages=29–49|issn=0105-2896|pmid=8132202|doi=10.1111/j.1600-065X.1993.tb00653.x|s2cid=45337367}}</ref> Because second-generation tolerance arises in the absence of any monoclonal antibodies to CD4 or CD8, it probably represents a natural response of the immune system, which, once initiated, becomes self-sustaining. This ensures the long duration of once induced tolerance, for as long as the donor antigens are present.<ref>{{Cite journal|last1=Qin|first1=S.|last2=Cobbold|first2=S. P.|last3=Pope|first3=H.|last4=Elliott|first4=J.|last5=Kioussis|first5=D.|last6=Davies|first6=J.|last7=Waldmann|first7=H.|date=1993-02-12|title="Infectious" transplantation tolerance|journal=Science|language=en|volume=259|issue=5097|pages=974–977|doi=10.1126/science.8094901|issn=0036-8075|pmid=8094901|bibcode=1993Sci...259..974Q|s2cid=40979501}}</ref>
== Mechanisms == thumb|upright=1.2|Treg migrate to the grafted tissue. Activated Treg convert ATP released by inflamed tissues to adenosine via the ectoenzymes CD39 and CD73. Local adenosine could contribute to the initial "privileged" microenvironment. Treg also secrete TGF-β and IL-10 which inhibit the maturation and migration of dendritic cells (DC). These "decommissioned" DC can secrete catabolic enzymes for depletion of essential amino acids (EAA) and, therefore, induce apoptosis of effector T cells. Moreover, the "privileged" tissues could release pro-apoptotic galectin-9 which binds to TIM-3 expressed by effector T cells such as Th1 and Th17. This further amplifies the immunosuppressive microenvironment. Each of these components within the graft can further reinforce the local anti-inflammatory state such that any naive T cell, migrating into this area, will be converted to induced Treg (iTreg) through infectious tolerance. The iTreg then expand and further suppress immunity in the "privileged" microenvironment. During a tolerant state potential effector cells remain but are tightly regulated by induced antigen-specific CD4+ regulatory T cells (iTregs). Many subsets of iTregs play a part in this process, but CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs play a key role, because they have the ability to convert conventional T cells into iTregs directly by secretion of the suppressive cytokines TGF-β, IL-10 or IL-35, or indirectly via dendritic cells (DCs).<ref>{{Cite journal|last1=Gravano|first1=David M.|last2=Vignali|first2=Dario A.A.|date=June 2012|title=The Battle Against Immunopathology: Infectious Tolerance Mediated by Regulatory T Cells|journal=Cellular and Molecular Life Sciences|volume=69|issue=12|pages=1997–2008|doi=10.1007/s00018-011-0907-z|issn=1420-682X|pmc=3353028|pmid=22205213}}</ref> Production of IL-10 induces the formation of another population of regulatory T cells called Tr1. Tr1 cells are dependent on IL-10 and TGF-β as well as Tregs, but differ from them by lacking expression of Foxp3.<ref>{{Cite journal|last1=Roncarolo|first1=Maria Grazia|last2=Gregori|first2=Silvia|last3=Battaglia|first3=Manuela|last4=Bacchetta|first4=Rosa|last5=Fleischhauer|first5=Katharina|last6=Levings|first6=Megan K.|authorlink=Maria Grazia Roncarolo|date=August 2006|title=Interleukin-10-secreting type 1 regulatory T cells in rodents and humans|journal=Immunological Reviews|volume=212|pages=28–50|doi=10.1111/j.0105-2896.2006.00420.x|issn=0105-2896|pmid=16903904|s2cid=21297026}}</ref> High IL-10 production is characteristic for Tr1 cells themselves and they also produce TGF-β.<ref>{{Cite journal|last1=Mekala|first1=Divya J.|last2=Alli|first2=Rajshekhar S.|last3=Geiger|first3=Terrence L.|date=2005-08-16|title=IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=102|issue=33|pages=11817–11822|doi=10.1073/pnas.0505445102|issn=0027-8424|pmc=1188008|pmid=16087867|bibcode=2005PNAS..10211817M|doi-access=free}}</ref> In the presence of IL-10 can be also induced tolerogenic DCs from monocytes, whose production of IL-10 is also important for Tr1 formation.<ref>{{Cite journal|last1=Gregori|first1=Silvia|last2=Tomasoni|first2=Daniela|last3=Pacciani|first3=Valentina|last4=Scirpoli|first4=Miriam|last5=Battaglia|first5=Manuela|last6=Magnani|first6=Chiara Francesca|last7=Hauben|first7=Ehud|last8=Roncarolo|first8=Maria-Grazia|date=2010-08-12|title=Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway|journal=Blood|volume=116|issue=6|pages=935–944|doi=10.1182/blood-2009-07-234872|issn=1528-0020|pmid=20448110|doi-access=free}}</ref> These interactions lead to the production of enzymes such as IDO (indolamine 2,3-dioxygenase) that catabolize essential amino acids. This microenvironment with a lack of essential amino acids together with other signals results in mTOR (mammalian target of rapamycin) inhibition which, particularly in synergy with TGF-β, direct the induction of new FoxP3 (forkhead box protein 3) expressing Tregs.<ref>{{Cite journal|last1=Cobbold|first1=Stephen P.|last2=Adams|first2=Elizabeth|last3=Nolan|first3=Kathleen F.|last4=Regateiro|first4=Frederico S.|last5=Waldmann|first5=Herman|date=July 2010|title=Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link|journal=Immunological Reviews|volume=236|pages=203–218|doi=10.1111/j.1600-065X.2010.00913.x|issn=1600-065X|pmid=20636819|s2cid=42889594}}</ref>
== See also == * Immune tolerance * Central tolerance * Peripheral tolerance * regulatory T cells * Immune response * Immune tolerance in pregnancy {{clear}}
== References == <references />
Biology Category:Immunology