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B cell depletion: a novel therapy for autoimmune diabetes?
Hélène Bour-Jordan and Jeffrey A. Bluestone
Diabetes Center, Department of Medicine, and Department of Pathology, UCSF, San Francisco, California, USA.
Address correspondence to: Jeffrey A. Bluestone, UCSF Diabetes Center, HSW 1118, Box 0540, 513 Parnassus Avenue, San Francisco, California 94143-0540, USA. Phone: (415) 514-1683; Fax: (415) 564-5813; E-mail: jbluest@diabetes.ucsf.edu.
Find articles by Bour-Jordan, H. in: JCI | PubMed | Google Scholar
Diabetes Center, Department of Medicine, and Department of Pathology, UCSF, San Francisco, California, USA.
Address correspondence to: Jeffrey A. Bluestone, UCSF Diabetes Center, HSW 1118, Box 0540, 513 Parnassus Avenue, San Francisco, California 94143-0540, USA. Phone: (415) 514-1683; Fax: (415) 564-5813; E-mail: jbluest@diabetes.ucsf.edu.
Find articles by Bluestone, J. in: JCI | PubMed | Google Scholar
Published December 3, 2007 - More info
J Clin Invest. 2007;117(12):3642–3645. https://doi.org/10.1172/JCI34236.
© 2007 The American Society for Clinical Investigation
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Abstract
The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell–depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.
Authors
Chang-yun Hu, Daniel Rodriguez-Pinto, Wei Du, Anupama Ahuja, Octavian Henegariu, F. Susan Wong, Mark J. Shlomchik, Li Wen
Type 1 diabetes (T1D) is an autoimmune disease targeting insulin-producing β cells in the pancreatic islets of Langerhans. Despite years of fundamental and clinical research, no cure has been found for this devastating disease. Thus, there is a growing interest in immunotherapies approved for other diseases that could be rationally investigated in T1D patients. In this regard, rituximab (Rituxan; Genentech), a humanized anti-CD20 mAb that induces B cell depletion and is FDA approved for B cell lymphoma therapy, is currently being assessed in a clinical trial in T1D. However, until recently, preclinical studies have been limited by the absence of anti-CD20 reagents that induce B cell depletion in mice. In this issue of the JCI, Hu et al. address this issue by generating transgenic NOD mice that express human CD20 on B cells (hCD20/NOD mice) (1). Treatment with a murine anti-CD20 mAb that targets the same epitope as rituximab rapidly induced complete B cell depletion in lymph nodes and bone marrow and partial depletion in the spleen, albeit with limited effects in the peritoneal cavity. Importantly, anti-CD20 therapy partially protected prediabetic hCD20/NOD mice from disease and restored euglycemia in one-third of new-onset diabetic mice. Furthermore, Hu et al. suggest that protection from disease is associated with the generation of Treg and regulatory B cell populations. Thus, the study by Hu et al. provides a proof of principle that supports the investigation of anti-CD20–targeting therapies in T1D, and the transgenic mouse created by these authors provides a useful model in which to examine further the mode of action of rituximab and second-generation anti-CD20 drugs in vivo.
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Role of B cells in autoimmune diabetes
The NOD mouse is a well-characterized model of autoimmune diabetes that is believed to exhibit many of the mechanisms underlying the pathogenesis of the human disease (10), and as such, it is likely instructive in examining the role of B cells in T1D. Mononuclear infiltrates in both NOD mouse and human islets comprise mainly CD4+ and CD8+ T cells, but B cells, NK cells, dendritic cells, and macrophages have been described (10–12). The central role of T cells in autoimmune diabetes was demonstrated in the NOD model by the ability of T cells to transfer disease and the protection afforded by immunotherapies targeting T cells (13–16). The precise function of autoreactive B cells has been more difficult to establish (Figure 1). Islet-specific autoantibodies targeting major autoantigens such as glutamic acid decarboxylase and insulin can be detected in the serum in NOD mice and in patients and have been an excellent indicator of autoimmunity and predictor of disease in diabetic patients and relatives (17, 18). However, a direct pathogenic role for autoantibodies is controversial. Greeley et al. reported that maternal autoantibodies are important for the development of disease in NOD mice (19), but diabetes cannot be transferred by autoantibodies. In NOD mice, the importance of B cells was clearly demonstrated by the dramatic reduction in insulitis and diabetes incidence following B cell depletion using anti-IgM antibodies at birth or in NOD mice genetically deficient in B cells (20). Evidence from many different studies suggests that B cells function as islet antigen–presenting cells for autoreactive T cells in NOD mice and that autoantibodies expressed on the cell surface improve the capture and presentation of autoantigens (21–24). Importantly, early loss of B cells does not eliminate insulitis in NOD mice, suggesting that autoreactive B cells may be essential at late stages of disease to enhance autoreactivity and promote epitope spreading (20, 21). This finding has significant clinical implications, since B cell–depleting therapies such as rituximab would be most useful in patients newly diagnosed with T1D or islet transplant recipients (25).
Figure 1Anti-CD20 therapy and B cells in autoimmunity. Autoreactive B cells play a role in autoimmune diseases via their production of circulating autoantibodies and/or their role as antigen-presenting cells for autoreactive T cells after the capture of self antigens by cell surface autoantibodies that increase their antigen-presentation capabilities (i). Rituximab and other anti-CD20 mAbs cross-link CD20 on the surface of B cells and induce B cell depletion mainly through ADCC, although complement-dependent cytotoxicity (CDC) and apoptosis have also been implicated (ii). Anti-CD20–mediated B cell depletion prevents interaction with autoreactive T cells (iii) and reduces the amount of circulating autoantibodies (iv), although with much slower kinetics. Finally, as suggested by Hu et al. in their study in this issue of the JCI (1), anti-CD20 therapy may induce Treg and regulatory B cell populations (CD4+Foxp3+ Tregs and transition type 2 [T2] B cells) that could play a role in restoring immune tolerance, possibly via the production of IL-10 (v).
Novel mAbs targeting murine CD20 and inducing B cell depletion have been developed recently (26), and transgenic mice expressing hCD20 in B cells have been generated on the FVB mouse genetic background (27) and now by Hu et al. (1) on the NOD background. Importantly, the extent and tissue variability of B cell depletion following anti-CD20 therapy appears similar in these models, suggesting that they may provide clinically relevant information. Most significantly, Hu et al. showed that anti-CD20 therapy in new-onset diabetic hCD20/NOD mice reversed diabetes in one-third of the treated mice, providing a much-needed experimental rationale for the investigation of rituximab in T1D, especially since clinical trials are already underway (28). It is unclear why only a third of mice became euglycemic, but the protocol followed by Hu et al., which consisted of waiting six days after diagnosis of diabetes before starting treatment, a time point when most residual islets have been destroyed, could have contributed to the low success rate. Indeed, in another therapeutic setting, we showed that it is critical to target mice with blood glucose lower than 350 mg/dl (29). Interestingly, in the Hu et al. study, the reversal of hyperglycemia was characterized by variable and generally slow kinetics but long-term effect. This could reflect the presence of two separate processes: a short-term antiinflammatory effect in islets, whose kinetics might depend on the aggressiveness of the autoimmune infiltrate, and a slower induction of regulatory cell population(s) that could induce long-term tolerance.
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