Therapeutic Targeting of B Cells and T Cells in Autoimmune Diabetes
Is It a Solution?
- INSERM U1013, Hôpital Necker-Enfants Malades, Paris, France
- Université Paris Descartes, Sorbonne Paris Cite, Paris, France
- Corresponding author: Lucienne Chatenoud, .
Insulin-dependent type 1 diabetes (T1D) is attributable to the destruction of pancreatic β-cells by autoreactive T lymphocytes (T cells). Antibodies to various β-cell autoantigens also are detected in T1D that are not pathogenic but represent excellent markers of β-cell destruction and are widely used to identify high-risk individuals (1,2). This by no means excludes a major role for B lymphocytes (B cells) in the development and progression of T1D. Serreze et al. (3) first showed that disease-prone nonobese diabetic (NOD) mice lacking B cells were completely protected from disease, a finding explained by the capacity of B cells to present autoantigens (4). Furthermore, B cells are essential for “antigen/epitope spreading,” a central mechanism underlying the chronicity of autoimmunity that is the progressive diversification of the autoimmune response from one epitope to another, expressed by the same or by a distinct autoantigen (i.e., intramolecular spreading compared with intermolecular spreading) (5,6). All this explains the therapeutic potential of monoclonal antibodies targeting B cells or their growth factors to halt progression of T1D in NOD mice (7–10). Thus, depleting antibodies directed to the CD20 B-cell antigen efficiently prevented disease when administered to prediabetic NOD mice and, although in a low proportion of animals, also temporarily reversed T1D once hyperglycemia was established (8). Importantly, a randomized placebo-controlled phase II study conducted established that in recent-onset T1D patients a single course of rituximab, a humanized CD20 monoclonal antibody, significantly preserved endogenous insulin secretion as compared with placebo (11). However, the effect was transient and the therapeutic benefit waned as B-cell numbers recovered, implying that “operational” immune tolerance, intended as the specific inhibition of the autoimmune response in absence of chronic …