Combination B-lymphocyte Depletion Treatment with Anti-CD20 and BAFF Blockade is No Superior to BAFF Blockade Alone in The NOD Model of Type 1 Diabetes

Abstract

Abstract While type 1 diabetes (T1D) is an autoimmune disease in which autoimmune destruction of pancreatic β cells is ultimately mediated by T-cells, in the NOD mouse model, and also likely humans B-lymphocytes also play a key pathogenic role. B-lymphocyte depletion either through antibody targeting CD20 or blocking their access to BAFF elicits strong T1D protection in NOD mice. However, whether the combined strategy of targeting both CD20 and BAFF could further improve therapeutic efficacy for T1D remained unknown. Currently humans at high future T1D risk can only be identified at late prodromal stages of disease indicated by markers such as insulin autoantibodies (IAA). We show BAFF blockade treatment commenced in already IAA positive NOD mice prevented progression to overt T1D, whereas anti-CD20 was ineffective as a mono- or co-therapy at this disease stage. While BAFF blockade depletes the majority of islet infiltrating B-lymphoctes, a memory-like subset remained, whose potential diabetogenic capacity needs further exploring. Although BAFF blockade treated mice are protected from T1D development, the severity of insulitis was not reduced. One complicating factor underlying the failure of anti-CD20 is that NOD mice developed neutralizing antibodies against the injected anti-CD20, and the degree of B-lymphocyte rebounding correlates with the titer of neutralizing antibodies present in the sera. The dual directed immunotherapy does not either improve the protection offered by BAFF blockade only, or reduce the severity of insulitis, despite the greater depletion on various B-lymphocyte subsets and further reduction on those that survived of MHC and CD40 molecules respectively involved in antigen presentation, and class switching.