Goal: To determine the mechanism(s) by which IgM immunotherapy restores immune homeostasis in Type 1 Diabetes (T1D).

Background: IgM immunotherapy prevents the onset and progression of T1D and in conjunction with islet transplantation, prevents its recurrence.

Methods: 5 wks-old NOD mice received intraperitoneal mouse or human IgM, saline or IgG (100[mu]g initially followed by 50–75[mu]g twice in a week) until 18 weeks of age. 2) 5 wks-old BL6 and NOD;VH125BL6 and VH125NOD; and humanized BLT mice received IgM on Days 1,3, 5 and 10. On Day13, splenocytes and bone marrow cells were harvested and analyzed by flow cytometry (FC).

Results: 90% of the saline-injected mice became diabetic in 20 weeks. In contrast, none that received IgM therapy became diabetic (p<0.0001). IgM expanded B cell numbers in spleens of NOD mice to BL6 levels (P<0.05), and doubled B cell activating factor BAFF levels. FC data analysis (viSNE) post-IgM therapy revealed an expanded myeloid derived suppressor cell (MDSC) population. IgM markedly reduced immature and mature recirculating B cell subsets, and the percentage of marginal zone B cells (subset associated with perpetuating autoimmunity) in bone marrow of NOD and Bl6 mice (p<0.05; p<0.001). IgM significantly increased the proportion of newly emergent transitional B cells in NOD mice (p<0.01) indicating normalization of B cell homeostatic defects. Increased levels of IgM Fc-Receptor (TOSO) expression by splenic transitional B cells indicates that IgM may interact with B lymphocytes via TOSO at this selection point. In VH125 NOD mice, IgM therapy eliminated insulin binding B cell population (p<0.05). IgM inhibited plasma insulin autoantibody levels in NOD mice indicating a reduction in autoreactive B cell activation. Increased levels of regulatory B cell phenotypes (CD86^LO, CD40+ ^LOTim-1^HI) were observed in the thymus along with expansion of thymic regulatory T cells (Tregs). Splenocytes and T regs from IgM treated mice transferred diabetes protection. Humanized BLT mice treated with human IgM also showed expansion of Tregs indicating the potential of therapeutic IgM.

Conclusions: IgM therapy restores immune homeostasis in T1D via expansion of the MDSC and Treg compartments and correction of the B cell lymphopenia that undermines immune selection in NOD mice. This beneficial effect may be translatable to patients with T1D or islet graft recipients as evidenced in our preclinical model of human immunology.

CITATION INFORMATION: Chhabra P, Wilson C, Moore D, Brayman K. IgM Immunotherapy Restores Immune Homeostasis in Type 1 Diabetes. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress