Tolerance an Overview. Birgit Sawitzki, PhD Institute of Medical Immunology, Charité University Medicine, Berlin, Germany

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1 Tolerance an Overview Birgit Sawitzki, PhD Institute of Medical Immunology, Charité University Medicine, Berlin, Germany

2 Immune tolerance Immune reactions Desired Undesired Tumour immunity Anti-infectious immunity Allergy Autoimmunity Transplantation

3 Balancing lymphocyte activation and control Activation Effector T cells Tolerance Regulatory T cells Normal: reactions against pathogens Inflammatory disease, e.g. reactions against self No response to self Controlled response to pathogens

4 General principles of controlling immune responses Responses against pathogens decline as the infection is eliminated Apoptosis of lymphocytes that lose their survival signals (antigen, etc) Memory cells are the survivors Active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumors and some chronic infections) Often grouped under tolerance

5 Immunological tolerance Definition: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen) Significance: All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy

6 Central and peripheral T and B cell tolerance The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called receptor editing ) Some CD4 T cells may differentiate into regulatory (suppressive) T lymphocytes From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007!

7 Central and peripheral T and B cell tolerance

8 Regulation of adaptive immunity compartments Mechanisms Therapeutic application central Thymus, negative selection Induction of natural occurring CD4 + CD25 + Tregs Induction of a chimerism Intrathymic injection of antigen periphery Route of antigen application Frequency of T cells Antigen load costimulatory signals suppression Oral tolerance T cell depletion TCR or co-receptor targeting blocking antibodies regulatory T and B cells

9 Central tolerance Lymphocytes that see self antigens before they are mature are either eliminated or rendered harmless Probably continues to occur at some level throughout life (as new lymphocytes are produced from bone marrow stem cells) Role of the AIRE protein in thymic expression of some tissue antigens

10 T cell tolerance central positive selection / negative selection + induction of naturally occuring CD4 + CD25 + regulatory T cells CD4- CD8- CD3- DN CD4+ CD8+ CD3+ DP CD4- CD8+ CD3+ CD4+ CD8- CD3+ CD4+ CD25+ CD3+

11 Central T cell tolerance apoptosis of self reactive T cells

12 Expression of tissue restricted proteins

13 Central T cell tolerance Induction of a mixed chimerism By infusing donor bone marrow allo-reactive recipient T-cell progenitor cells are being deleted as part of the negative selection within the thymus.

14 B10.A (H-2 a ) Bone marrow + anti-cd40l / CTLA4Ig B10.A (H-2a) skin C57BL/6 (H-2 b ) survival detection of chimerism Wekerle et. Al. Nat. med. 2000

15 Clinical trials mixed chimerism 200cGy total body Leventhal et al. Sci Transl 2012 Tacrolimus + MMF Fludarabine + Cyclophoshamide days several HLA MM FCR = HSC + tolerance promoting facilitating cells (e.g. p-predcs) 8 patients enrolled, in 5 immunosuppression was discontinued 5 patients showed permanent macrochimerism pancytopenia, no signs of anti-donor mabs

16 Clinical trials mixed chimerism signs of immunodeficienc y - true tolerance? Page 11 9

17 Central B cell tolerance (BM) apoptosis or receptor editing first and second checkpoints

18 Central B cell tolerance (BM) apoptosis or receptor editing H. v. Boehmer Nature Immunology VpreB-Cλ5-V H -C H -stroma interaction mediates positive and negative selection of prebcrs via R + - Y - binding 2. Presentation of autoantigen by natural IgM and complement mediates negative selection of BCRs

19 Regulation of adaptive immunity compartments Mechanisms Therapeutic application central Thymus, negative selection Induction of natural occurring CD4 + CD25 + Tregs Induction of a chimerism Intrathymic injection of antigen periphery Route of antigen application Frequency of T cells Antigen load costimulatory signals suppression Oral tolerance T cell depletion TCR or co-receptor targeting blocking antibodies regulatory T and B cells

20 Peripheral tolerance Normal T cell response APC CD28 TCR T cell Activated T cells Anergy APC TCR Off signals Functional unresponsiveness Deletion APC Activated T cell Apoptosis (activation-induced cell death) Suppression APC Block in activation Regulatory T cell

21 T cell anergy

22 T cell anergy Multiple mechanisms demonstrated in different experimental systems No clear evidence that natural self antigens induce T cell anergy (especially in humans) Therapeutic potential: can we administer antigens in ways that induce T-cell anergy?

23 Regulation of adaptive immunity compartments Mechanisms Therapeutic application central Thymus, negative selection Induction of natural occurring CD4 + CD25 + Tregs Induction of a chimerism Intrathymic injection of antigen periphery Route of antigen application Frequency of T cells Antigen load costimulatory signals suppression Oral tolerance T cell depletion TCR or co-receptor targeting blocking antibodies regulatory T and B cells

24 Regulation of adaptive immunity oral tolerance Oral tolerance is defined as the lack of a systemic inflammatory / effector immune response following parenteral immunization

25 Regulation of adaptive immunity oral tolerance Gut Associated Lymphoid Tissue (GALT: Lamina propria LP, Peyer s Patches PP, Mesenteric Lymph nodes MLN) ensures homeostasis towards commensal bacteria and food antigens

26 Regulation of adaptive immunity oral tolerance 2. GALT contains specialized cells for antigen uptake: M cells (specialized intestinal epithelial cells) 2. Lamina propria DCs (extending processes) 3. transcellular / paracellular uptake of soluble antigen by epithelial cells

27 Regulation of adaptive immunity oral tolerance high production of anti-inflammatory cytokines e.g. TGFß and IL-10 lack of activating costimulatory molecules, but increased expression of neg. reg. molecules e.g. PD-L2 (anergy) local induction of regulatory T cells (both Foxp3 - and Foxp3 + ) especially by CD103 + DCs RA and TGFß are crucial for the induction of Tregs

28 Regulation of adaptive immunity oral tolerance Antigen load influences oral tolerance mechanism: low dose: regulation / suppression high dose: depletion / anergy

29 Regulation of adaptive immunity compartments Mechanisms Therapeutic application central Thymus, negative selection Induction of natural occurring CD4 + CD25 + Tregs Induction of a chimerism Intrathymic injection of antigen periphery Route of antigen application Frequency of T cells Antigen load costimulatory signals suppression Oral tolerance T cell depletion TCR or co-receptor targeting blocking antibodies regulatory T and B cells

30 Activation-induced cell death : death of mature T cells upon recognition of self antigens From Abbas and Lichtman. Basic Immunology 2nd ed, 2006! Both pathways cooperate to prevent reactions against self