Understanding Immune Tolerance Mechanisms: Key Concepts and Therapies

1. IMMUNE TOLERANCE • Lack of immune response to self antigens or innocuous non-self antigens • Not an immunodeficiency leading to infections • Antigen-specific unresponsiveness • Acquired characteristic induced by multiple mechanisms • Time dependent • Antigen concentration dependent

2. T K.L. McCoy

3. DELETION • Autoreactive cells killed • Negative selection in thymus Main mechanism of central tolerance Mediated by dendritic cells & macrophages • Activation-induced cell death Peripheral tolerance mechanism T cells die during an immune response Mediated by Fas pathway

4. IMMUNE PRIVILEGED SITES • Lack of immune response to allografts • Include fetus, brain, anterior chamber of eye • Lymphocytes have access and self antigens exit • Lack conventional lymphatic vessels • Rich in inhibitory molecules

5. ANERGY • Peripheral tolerance mechanism • Cells remain alive • Not capable of responding to antigen • Cells functionally inactivated • Long-lasting effect

6. ANERGY • Lack of co-stimulatory signals No CD28 signal renders T cells unable to produce IL-2 • CTLA-4 generates negative signal Blocks IL-2 production • Analog peptides act as partial agonist and generate negative signal • Disruption of CD4 or CD8 co-receptors impairs primary signal

7. SUPPRESSION • Hallmark Feature: Adoptively transferred with T cells • Also called Infectious tolerance • Regulatory CD4+ CD25+ T cells - Most important • Release of soluble cytokine receptors • Immune Deviation - Change Th1 to Th2 response or reverse

8. REGULATORY T CELLS • Constitutively express CTLA-4 • Function depends on CTLA-4 • Express antigen-specific MHC class II-restricted T cell receptor • Inhibitory cytokines include IL-4, IL-10 and TGF-b • Patients with mutated FoxP3 lack regulatory T cells and develop fatal multi-organ autoimmune disease

9. Two Roles of CTLA-4 in Tolerance • Delivers negative signal to CD8+ cytotoxic T cells and classical CD4+ helper T cells • Overrides positive signals through T cell receptor and co-stimulatory molecules • Critical for function of regulatory T cells that suppress autoimmune responses • CTLA-4 defects cause massive proliferation of classical helper T cells and systemic autoimmune disease

10. IMMUNOLOGICAL IGNORANCE • Peripheral tolerance mechanism • Cells are alive and capable of responding • Cells are “ignorant” of antigen and do not respond • Occurs if TCR has relatively low affinity and/or antigen concentration is low • Increase in antigen concentration may lead to a response

11. IMMUNOTHERAPY • Manipulation of immune tolerance • Induction to stop or prevent detrimental immune responses • Autoimmune diseases, allergies & graft rejection • Breakage to cause or boost an immune response • Cancer

12. PROMISING IMMUNOTHERAPIES • Peptide agonists to treat allergies • Anti-B7 antibodies to prevent graft rejection • Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection • Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis • Soluble TNF receptor to treat autoimmune diseases • Th1 cytokines to treat IgE-mediated allergies • Anti-CTLA-4 antibody to boost T cell responses to tumors • Killed tumors expressing B7 genes