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Tolerance Induction by Teplizumab Is Modulated by Gut Microbiota

Thursday, June 15
5:45 PM - 7:00 PM

We have shown that teplizumab, a non-FcR binding anti-CD3 mAb, induces tolerance by activating tolerogenic, IL-10 producing T cells in the gut of normal and humanized mice. Clinical studies revealed that not all patients respond to teplizumab treatment. Due to the intimate relationship between the immune system and microbiota in the gut, we hypothesized that gut microbiota can affect the efficacy of teplizumab treatment.
We studied the effects of modulating the gut microbiome on the prevention of xenograft rejection in humanized mice.
Teplizumab treatment delayed the rejection of B6 skin grafts on humanized NSG mice (p=0.001) and induced IL-10 secretion in the serum. Treatment with a cocktail of 4 antibiotics (Ampicillin, Neomycin, Metronidazole, and Vancomycin) but not the individual antibiotics prevented the activity of teplizumab and the induction of IL-10 (p=0.034). Teplizumab induced immune cell activation in gut infiltrating immune cells that was reduced when antibiotics were given. To directly study the activation properties of the microbiota of antibiotic-treated or untreated mice, we cultured splenocytes with microbiota and determined the cytokine production. Gut microbiota from antibiotic-treated mice induced less IL-10 production by splenocytes from humanized mice(p=0.0014). Moreover, human stool samples from antibiotic treated children also showed reduced induction of IL-10 by peripheral blood mononuclear cells.
In conclusion, our results suggest that the microbiota are critical modulators of tolerance induced by biologics. The microbiome from antibiotic humans induce less activation of human immune cells that is needed for acquisition of tolerance.

Elke Gulden

Associate Research Scientist
Immunobiology / Yale

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    Nalini Vudattu

    Immunobiology

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      Songyan Deng

      Yale University

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        Paula Preston-Hurlburt

        Yale University

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          Kevan Herold

          Professor of Immunology
          Department of Immunobiology and Internal Medicine, Yale University

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