Increased T Cell Proliferative Responses to Islet Antigens Identify Clinical Responders to Anti-CD20 Monoclonal Antibody (Rituximab) Therapy in Type 1 Diabetes

Abstract

Type 1 diabetes mellitus (T1DM) is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte antibody can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease- associated target antigens, and C-peptide levels of participants that did (responders) or did not (non-responders) show signs of β-cell preservation one year after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after 4 weekly doses of mAb. T cell proliferative responses to diabetes –associated antigens were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 months (58%), the proliferative responses to diabetes associated total (p=0.032), islet-specific (p=0.048), and neuronal auto-antigens (p=0.005) increased over the 12 month observation period. This relationship was not seen in placebo treated patients. We conclude that in patients with T1DM, anti-B cell mAb causes increased proliferative responses to diabetes antigens and attenuated β cell loss. The way in which these responses affect the disease course remains unknown.

The elusive role of B lymphocytes and islet autoantibodies in (human) type 1 diabetes

“…Another possibility is that, through the decline in B lymphocytes, a niche was created for repopulation of regulatory T cells (Tregs) or regulatory B lymphocytes [36]. Indeed, extensive phenotypic analysis of blood cells revealed transitional B lymphocytes as the single correlate of clinical efficacy of rituximab [37]. This latter finding could point to an immunoregulatory role for B lymphocytes in the pathogenesis of type 1 diabetes ('smoke'), rather than painting them as a pathogenic immune cell ('fire'), which is in accordance with the finding that type 1 diabetes may develop in spite of B lymphocyte deficiency.…”

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

“…T cells specific for a panel of b cell autoantigens (Herold et al 2011). The elevated b cell-specific reactivity is selective, since no difference is seen in T cell responses to control antigens.…”

“…Treg numbers is also detected within the first 10 weeks of therapy (Herold et al 2011). An additional study shows that rituximabinduced B cell depletion has a marked effect on follicular helper T cells (Tfh) in T1D subjects (Xu et al 2013).…”

Biomarkers in type 1 diabetes

“…Surprising results have also emerged from studies of antigen specific T cells. In the rituximab trial of patients with new onset T1D, the T cell proliferation response to diabetes-associated islet specific and neuronal antigens increased over 12 months in responders, but did not change in the non-responders(36). …”