Reversing Type 1 Diabetes The immunotherapy employs “nondepleting antibodies” that bind to and modify the activity of T cells mediating b cell-destruction.  Diabetes is rapidly reversed in NOD mice.  Remission is maintained indefinitely.  “Normal” T cell-mediated immunity is unaffected. Type 1 diabetes (T1D): an autoimmune disease resulting in destruction of the insulin producing b cells found in the islets of the pancreas. Immunotherapy Immunotherapy+ b cell replacement Islet b cells (insulin+) b cells T cells (CD4+ and CD8+ T cells) Autoreactive T cells are present in healthy individuals Autoreactive T cells “Pathogenic” CD4+ and CD8+ T cells Tissue inflammation and destruction Protective “immunoregulatory” T cells block tissue destruction by “pathogenic” T cells Autoreactive T cells Immunoregulatory T cells (Treg) Pathogenic CD4+ and CD8+ T cells Tissue inflammation and destruction Efficient b cell destruction occurs due to failure of islet resident Treg to block the activity of pathogenic T cells Islet ✚ ✚ ✚ b cells ✚ ✚ Preclinical T1D Pathogenic T cells ✚ ✚ ✚ Clinical T1D Three keys to establishing long-term remission in recent onset T1D 1. Eliminate pathogenic T cells found in the islets 2. Increase Treg to maintain long-term protection 3. “Normal” immunity is unaffected Anti-T cell (CD3) antibodies exhibit efficacy in recent onset diabetic patients Recent onset diabetic individuals receiving antiCD3 antibody (teplizumab, otelixizumab) exhibit maintained b cell function (but in the absence of remission). Protection attributed to depletion of autoreactive T cells and possibly an increase in Treg. Limitations: Protection is short-term. Nonautoreactive T cells are also depleted. Nondepleting anti-T cell (CD4/CD8) antibody therapy for the treatment of T1D Nondepleting (ND) antibodies bind to cells without initiating events that lead to lysis. Depending on the protein bound by the ND antibody, the activity of the cell can be modified. Waldmann et al. demonstrated that coadministration of ND anti-CD4 and -CD8 antibodies blocked rejection of transplanted tissues in mice. Transplant rejection typically involves a highly potent T cell response. Recent onset diabetic (<10 days) NOD mice. Blood glucose >250 mg/dl Remission? How long? 48 hrs ND anti-CD4 + antiCD8 antibodies Nondepleting anti-CD4/CD8 antibodies induce diabetes remission DIABETIC Antibodies no longer detected NONDIABETIC Blood glucose (mg/dl) 600 500 400 300 200 100 Long-term Maintenance of Remission: 19/20 (95%) -2 st po 72 h Remission Induction: 20/24 (83%) Pr io rt o nd YT S YT S 0 T cells x106 T cells x104 Induction of remission involves T cell “purging” of the pancreas within 6 days of treatment 10 8 6 4 2 0 50 Control Anti-CD4/CD8 Thy1.2+ T cells Control * Pancreas Control Anti-CD4/CD8 Anti-CD4/CD8 25 0 * Spleen Insulin 6 days post-treatment Long-term remission: a role for Treg? Antibodies not detected Treg are increased in long-term remission mice 8 4 T cells x104 0 10 5 0 Control Anti-CD4/CD8 * Pancreas Control Anti-CD4/CD8 * Pancreas Treg x104 Treg x104 150 days post-treatment 100 75 50 25 0 Control Anti-CD4/CD8 * Spleen ND anti-CD4/CD8 antibodies have NO effect on “normal” immunity Normal viral clearance 2 days later challenged with Lymphocytic choriomeningitis virus (LCMV) T cells x105 Control versus ND anti-CD4/CD8 4 Control Anti-CD4/CD8 2 0 -LCMV +LCMV Summary: ND anti-CD4/CD8 therapy induces rapid and long- term remission of diabetes by purging the pancreas of T cells and increasing Treg, respectively. Protection mediated by ND anti-CD4/CD8 is selective, affecting b cell autoimmunity but not normal immunity. ACKNOWLEDGEMENTS Tisch Lab Ramiro Diz Greg Gojanovich Mark Johnson Charles Kroger Fatima Manzoor Maurice Morillon Aaron Martin Nick Spidale Bo Wang Zuoan Yi Rui Zhang UNC-CH Maureen Su U Mass Michael Brehm Dale Greiner Funding Juvenile Diabetes Research Foundation National Institutes of Health