Tu122 - Enrichment of PD-1+TIGIT+ CD4 Effector Memory Cells After Alefacept Treatment in Type 1 Diabetes

Laura Cooney – Immune Tolerance Network; Elisavet Serti – Immune Tolerance Network; Duangchan Suwannasaen – Benaroya Research Institute; Kristina Harris – Immune Tolerance Network; Mark Anderson – Immune Tolerance Network; Cate Speake – Benaroya Research Institute; Gerald Nepom – Immune Tolerance Network; Srinath Sanda – Immune Tolerance Network; Alice Long – Benaroya Research Institute

Abstract Text: Determining optimal dosage remains a challenge for the development of immunomodulatory therapies in heterogenous patient populations. Type 1 diabetes (T1D) is a polygenic autoimmune disease in which pancreatic insulin-producing beta cells are destroyed. Two 12-week courses of alefacept, an LFA3-Ig fusion protein that binds to CD2, preserved residual beta cell function over 2 years, demonstrating clinical efficacy in T1D subjects in the Immune Tolerance Network T1DAL study. Treatment depleted CD2 high effector memory T cells (TEM) via antibody-dependent cellular cytotoxicity. Concomitant preservation of CD2 low regulatory T cells (Treg) resulted in a >75% increase in the Treg:TEM ratio in 82% of treated subjects at week 12. This is consistent with the proposed mechanism of action of alefacept. We also found that CD4 TEM co-expressing the inhibitory receptors PD-1 and TIGIT increased following this depletional therapy. PD-1+TIGIT+ TEM increased as a proportion of TEM by 20% at 12 weeks in 80% of subjects and persisted for over a year (30 treated, 12 placebo, p≤0.011). In vitro coculture of PD-1 negative CD4 T cells with alefacept did not induce PD-1 expression. In contrast, PD-1+TIGIT+ TEM were CD2 low with increased proliferation (Ki67) after treatment. Both before and after treatment, PD-1+TIGIT+ TEM secreted low levels of pro-inflammatory cytokines IL2, IFNgamma, and TNFalpha. Together these data suggest that alefacept may promote expansion of hyporesponsive PD-1+TIGIT+ TEM. Thus, increases in two complementary regulatory phenotypes (Treg:TEM ratio and PD-1+TIGIT+ TEM) may reflect pharmacodynamic effects of alefacept treatment and could guide dosage decisions for CD2-depleting therapies.