How does B-cell tolerance contribute to the protective effects of diabetes following induced mixed chimerism in autoimmune diabetes?

In type 1 diabetes, autoimmune-mediated damage and destruction of insulin-producing b-cells lead to a raised blood glucose. Glucose itself is toxic and some recovery of b-cell function is expected in the honeymoon phase after insulin treatment is instituted, but it was previously believed that all b-cells will ultimately be lost. In fact, there are individuals who continue to have some functioning b-cells, even many years after the onset of type 1 diabetes (1,2). This raises the hope that treatment to induce replication or regeneration of b-cells could be instituted in patients with long-standing diabetes, and makes it even more imperative that means of halting autoimmunity are found. Although nonmyeloablative autologous stem cell transplantation has been carried out, with long-term insulin independence successfully achieved in type 1 diabetes (3,4), many would feel that the risk-benefit ratio of this treatment is not acceptable for general use. Many other strategies, both nonantigenand antigen-specific therapies, have been trialed in patients with new-onset type 1 diabetes, but none, as yet, has provided a long-term solution to the autoimmune attack on remaining b-cells (5). However, short-term slowing of b-cell loss was seen with T-cell2targeted therapy using nondepleting antiCD3 (6,7), which was shown to temporarily reduce T cells, but, more importantly, to increase T-cell regulation. In addition, anti-CD20 treatment (rituximab) that targets B cells also temporarily slowed loss of endogenous insulin production (8,9), and currently there is a move to consider therapies that may be combined in order to achieve improved results. Racine and colleagues have developed a strategy to stop autoimmunity by induction of mixed chimerism in NOD mice. The treatment uses a nonablative therapy comprising nonmyeloablative conditioning with anti-CD3 and anti-CD8 monoclonal antibodies, followed by infusion of major histocompatibility complex-mismatched bone marrow and CD4-depleted spleen cells (10). This therapy is combined with gastrin and epidermal growth factor, and Racine et al. (11) have shown that not only is tolerance induced but also return of b-cells is demonstrated. They have previously shown that T-cell tolerance is induced by this means, but in this issue, Racine et al. (12) suggest that B-cell tolerance is also an essential component of the effectiveness of the treatment. Figure 1 illustrates B-cell processes that contribute to type 1 diabetes, and therefore why this subset of lymphocytes should be considered in immunotherapeutic targeting strategies. Racine et al. (12) have taken care to show effects not only on preexisting B cells but also on newly developing B cells. Following induction of tolerance and the infusion of the major histocompatibility complex-mismatched bone marrow, they depleted preexisting autoreactive B cells that included CD19CD138 preplasma and CD19CD138 plasma cells, among which are cells that can produce autoantibodies. Anti-insulin antibodies were reduced, although total immunoglobulin G was maintained in the treated mice. Other changes in B-cell subsets were documented, including a rise in immature B cells in the bone marrow, but a decrease in recirculating mature B cells. In addition, NOD mice have a lower proportion of T1 transitional (CD24CD21) and higher proportion of T2 transitional (CD24CD21CD23) B cells compared with C57BL/6 mice. However, after treatment, an increased ratio of T1/T2 cells in treated mice was dominated by donor T1 B cells, as found in normal C57BL/6 mice.