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Most T cells against self eliminated by central Most T cells against self eliminated by central tolerance; but a few escape.tolerance; but a few escape.

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LYMPHOCYTES REGOGNIZING EITHER SELF LYMPHOCYTES REGOGNIZING EITHER SELF OR NONSELF MUST LIMIT THEIR RESPONSE!OR NONSELF MUST LIMIT THEIR RESPONSE!

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DC Mediated Tolerance:DC Mediated Tolerance: In absence of danger signals, DCs that have engulfed only self antigens, have no In absence of danger signals, DCs that have engulfed only self antigens, have no

costim molecules, will “tolerize” Th cells.costim molecules, will “tolerize” Th cells. DC cells seem to develop “tolerizing ability” DC cells seem to develop “tolerizing ability” Causes either apoptosis of Th cell, or anergy.Causes either apoptosis of Th cell, or anergy.

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B cell toleranceB cell tolerance Since Th cells against self antigens should not exist, B cells binding Since Th cells against self antigens should not exist, B cells binding

self antigens cannot be activated.self antigens cannot be activated.– Become anergic;Become anergic;

– Eventually apoptose as do all unstimulated B cellsEventually apoptose as do all unstimulated B cells

Somatic hypermutation can create B cell clones against self; but Somatic hypermutation can create B cell clones against self; but become anergic.become anergic.

T cells don’t have somatic hypermutation.T cells don’t have somatic hypermutation.

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Treg cells Treg cells generatedgenerated by negative selection in thymus by negative selection in thymus Up regulation of Foxp3 transcription Up regulation of Foxp3 transcription

factor and then develop into Treg cells.factor and then develop into Treg cells. High CD4 and CD25High CD4 and CD25

Once Treg binds to tolerogenic DC, Once Treg binds to tolerogenic DC, becomes “anergic”, and can now block becomes “anergic”, and can now block proliferation of ANY CD4 T cells, of proliferation of ANY CD4 T cells, of any antigen specificity, through direct any antigen specificity, through direct contact with the T cell.contact with the T cell.

This tolerance dominant, can be This tolerance dominant, can be transferred by T cells.transferred by T cells.

““NOD” [non-obese diabetic] mice NOD” [non-obese diabetic] mice injected w normal CD4+ T cells do not injected w normal CD4+ T cells do not come down with diabetes.come down with diabetes.

2-10% of CD4 T cells; CD25+2-10% of CD4 T cells; CD25+ Depletion of these T-reg cells increases Depletion of these T-reg cells increases

immune response to self or graft; normal immune response to self or graft; normal mice develop diabetes.mice develop diabetes.

Clincal uses?Clincal uses?

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TOLERANCE INDUCING CONDITIONS:TOLERANCE INDUCING CONDITIONS:– High OR low doses of antigenHigh OR low doses of antigen

– Persistance of antigenPersistance of antigen

– I.V. or Oral introductionI.V. or Oral introduction

– Blocking of costim signal.Blocking of costim signal.

Antigen given orally leads to toleranceAntigen given orally leads to tolerance Mice fed insulin are protected from diabetes; MBP resistant to EAEMice fed insulin are protected from diabetes; MBP resistant to EAE However, similar studies in humansHowever, similar studies in humans

– have been unsuccessful.have been unsuccessful. May be more successful in preventingMay be more successful in preventing

– ONSET of disease than treating.ONSET of disease than treating.

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IMMUNE PRIVILEGED SITESIMMUNE PRIVILEGED SITES CNSCNS EyesEyes TestesTestes Eliminate activated T cells by Fas-L expressed in these sites.Eliminate activated T cells by Fas-L expressed in these sites.

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Maternal-Fetal ToleranceMaternal-Fetal Tolerance HOW WOULD YOU design a system to tolerate fetal antigens on HOW WOULD YOU design a system to tolerate fetal antigens on

placenta?placenta? Will accept graft from fetal MHC type during pregnancy; so it’s not Will accept graft from fetal MHC type during pregnancy; so it’s not

just local.just local. Reactivity returns after birth.Reactivity returns after birth. Treg cellsTreg cells Placenta nearly devoid of MHC-1Placenta nearly devoid of MHC-1 Only ‘MHC’ produced are non-polymorphic HLA-E and HLA-G, Only ‘MHC’ produced are non-polymorphic HLA-E and HLA-G,

which suppress maternal NK cells.which suppress maternal NK cells.

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NEONATAL TOLERANCENEONATAL TOLERANCE Lifelong tolerance if bone marrow and/or spleen cells introduced to Lifelong tolerance if bone marrow and/or spleen cells introduced to

neonates.neonates. Perhaps presenting antigen in thymus?Perhaps presenting antigen in thymus?

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EXPERIMENTAL TOLERANCEEXPERIMENTAL TOLERANCE Can be easily induced in neonates, or adults with immune system Can be easily induced in neonates, or adults with immune system

weakened by irradiation or chemoweakened by irradiation or chemo Even after immune system recovers, tolerance to new antigens Even after immune system recovers, tolerance to new antigens

maintained.maintained.

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QUESTIONS YOU SHOULD BE ABLE TO QUESTIONS YOU SHOULD BE ABLE TO ANSWERANSWER

iNTRO: #1iNTRO: #1A: #1-3,5A: #1-3,5B.II-IV: #3B.II-IV: #3C: #1,2C: #1,2D: #1-5D: #1-5