George S Eisenbarth

Publications (2)28.25 Total impact

• Article: In vivo BLyS/BAFF neutralization ameliorates islet-directed autoimmunity in nonobese diabetic mice.

  Ghazal Zekavat, Susan Y Rostami, Armen Badkerhanian, Ronald F Parsons, Brigitte Koeberlein, Ming Yu, Christopher D Ward, Thi-Sau Migone, Liping Yu, George S Eisenbarth, Michael P Cancro, Ali Naji, Hooman Noorchashm
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  ABSTRACT: B lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B cell compartment reduces the competitive constraint on the entry of newly emerging TR B cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. In this study we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TR-->FO selection by increasing TR B cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone B lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TR-->FO checkpoint, 2) abrogated serum insulin autoantibodies, 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction, and 6) disrupted CD4 T cell activation in NOD mice. Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.
  The Journal of Immunology 12/2008; 181(11):8133-44. · 5.79 Impact Factor
• Article: Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.

  Siri Atma W Greeley, Makoto Katsumata, Liping Yu, George S Eisenbarth, Daniel J Moore, Heidi Goodarzi, Clyde F Barker, Ali Naji, Hooman Noorchashm
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  ABSTRACT: The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.
  Nature Medicine 05/2002; 8(4):399-402. · 22.46 Impact Factor