Naturally occurring immunoglobulin M (nIgM) autoantibodies prevent autoimmune diabetes and mitigate inflammation after transplantation.

Autoimmune type 1 diabetes mellitus (T1D) is a multifactorial disease caused by the progressive destruction of insulin-producing pancreatic β-cells that results in an absolute loss of insulin production.1,2 Prevention or reversal of T1D either by preventing or arresting autoimmunity or through restoration of β-cell mass and function is the ultimate goal of clinical intervention. Diagnosis of the disease in the later stages of prehyperglycemic β-cell destruction restricts the types of immunotherapies that can be implemented. To date, pancreas and islet transplantation remain the only reliable cures of diabetes that have met with consistent success.3,4 However, the requisite chronic immunosuppressive therapy with its deleterious diabetogenic and nephrotoxic side effects, such as the risk associated with global deletion of T cells and the development of infections and malignancies, remains the Achilles’ heel of therapeutic interventions aimed at improving islet graft survival and preventing autoimmune diabetes.5,6 Another major drawback of chronic immunosuppressive therapy is its ineffectiveness over the long term that results in recurrence of disease upon drug withdrawal. Therefore, the development of novel therapeutic interventions that can prevent autoimmune-and alloimmune-mediated β-cell destruction by establishing effective chronic immunological unresponsiveness in the absence of chronic immunosuppression, with minimal or no deleterious side effects, is the principal focus of ongoing multidiscipliniary research. Current efforts to this end have not met with much clinical success. Repertoires of naturally occurring autoantibodies have been intensively studied during the last 3 decades and thought to play a significant role in the immunology of health and disease. These autoantibodies are predominantly of the IgM isotype and can be found in umbilical cord blood along with the long-lived, self-renewing B-1 lymphocytes that produce them, before exposure to foreign antigens; hence, referred to as naturally occurring or natural IgM (nIgM).7,8 nIgMs and a subset known as nIgM anti-leukocyte autoantibodies (nIgM-ALAs) are present at low levels in normal individuals and increase during inflammatory disorders and various infections.9 Previous studies in our laboratory and others have demonstrated that polyclonal serum nIgM and nIgM-ALA are a heterogeneous group of antibodies that are reactive to autologous and allogeneic cells with specificities for different, largely undefined membrane receptors that include receptors with phospholipids, glycolipids, and glycoproteins, and other cells that express leukocyte receptors.7–10 Encoded by minimally or nonmutated germ line genes, nIgMs are characteristically polyreactive with low-binding affinity. Of particular importance, these autoantibodies do not mediate cytolysis in the presence of complement at body temperature and differ from disease-producing autoantibodies in that the latter are predominantly of the IgG isotype that bind with high affinity and specificity to autoantigens and mediate cytolysis at 37°C. Elevated levels of nIgM-ALAs have been associated with lower incidence and severity of acute human heart and kidney graft rejections, thus permitting better graft survival.10–12 We have previously shown that nIgM-ALA plays a regulatory role in attenuating inflammation mediated by innate and adaptive immune mechanisms, including where the inflammatory response involved Th-17 cells that were not effectively regulated by regulatory T cells.10 In addition, purified human serum nIgM immunoprecipitated human CD3 and CD4 T cells and chemokine receptors CCR5 and CXCR4 from whole-cell lysates, downregulated CD2, CD86, and CD4, inhibited leukocyte production of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-13, and IL-2, and inhibited T-cell activation and proliferation as well as leukocyte chemotaxis induced by chemokines, indicating an innate mechanism that acts to downregulate T-cell–mediated inflammatory responses.7–10 Polyclonal nIgMs have also been shown to contribute to the maintenance of immune homeostasis and prevent autoimmunity.13,14 These findings prompted us to (a) investigate whether purified, polyclonal mouse serum nIgM autoantibody therapy could have a functional role in inhibiting the onset and progression of T1D when administered in a nonobese diabetic (NOD) mouse model of autoimmune T1D, (b) determine whether intervention at the prehyperglycemic late stage of disease development or after the establishment of overt diabetes might be feasible, and (c) investigate whether administration of nIgM could prolong graft survival after syngeneic and allogeneic islet transplantation by mitigating inflammation.