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Poster Sessions: Basic: The World Transplant Congress 2014 Abstract Supplement is jointly published by the American Journal of Transplantation and Transplantation on behalf of the American Society of Transplant Surgeons, The Transplantation Society and the American Society of Transplantation.: Islet Cell and Cell Transplantation: Tuesday, July 29, 2014: 9: 30 AM - 6: 30 PM: Exhibit Hall

Antigen-Specific Therapy With Human Proinsulin and IL10 in Combination With Short-Course Monoclonal CD3 Antibody in Preclinical Models of Islet Transplant.

Abstract# C1702

Mori da, Monteiro J. Carvalho1; Takiishi, T.1; Van Belle, T.1; Korf, H.1; Rottiers, P.2; Steidler, L.2; Gysemans, C.1; Mathieu, C.1

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Beta-cell replacement into a diabetic patient with pre-existing immunity to islet auto-antigens (Ags) results in autoimmunity recurrence after islet transplantation. Anti-CD3 monoclonal antibodies remain the most promising immune therapy for reversing type 1 diabetes but lack antigen-specificity. Induction of Ag-specific tolerance by auto-Ag peptides/proteins delivered to the gastrointestinal tract by genetically-modified food-grade lactic acid bacterium Lactococcus lactis (L. lactis) represents an attractive alternative approach but its therapeutic efficacy in islet transplantation remains to be determined. The present study investigated whether a short-course sub-therapeutic dose of monoclonal CD3 antibody (anti-CD3) alone or combined with mucosal administration of L .lactis secreting human pro-insulin (PINS) together with IL10 could arrest recurrent autoimmunity in transplanted non-obese diabetic (NOD) mice. Longstanding-diabetic NOD mice (2-3 weeks post-diagnosis) received 500 syngeneic insulitis-free islets under the kidney capsule and were subsequently injected with anti-CD3 (145-2C11 clone, 2.5 μg/d) i.v for 5 consecutive days and gavaged during 6 weeks with L.lactis-PINS+IL10 (2 × 109 CFU). Combining anti-CD3 with L.lactis-PINS+IL10 maintained graft function in 57% of diabetic recipients (n=7; 2 weeks post-diagnosis) compared to 37% in mice under anti-CD3 mono-therapy (n=11). Three weeks post-diagnosis, the combination therapy was successful in 42% of islet-transplanted mice (n=12) compared to 25% of mice receiving anti-CD3 alone (n=8). Normoglycemia was maintained long-term (>16 weeks post-transplantation). Each of the anti-CD3-based therapies increased the frequency of CD4+(CD25+)Foxp3+ T regulatory cells locally in the kidney-draining lymph nodes. These results demonstrate that orally-administered non-pathogenic and non-colonizing L.lactis modified to secrete whole human PINS and IL10 can maintain normal blood glucose levels in islet-transplanted longstanding diabetic NOD mice when introduced in the window of opportunity for tolerance created by low-dose systemic anti-CD3 mAb.

DISCLOSURES:Rottiers, P.: Employee, Actogenix, Stockholder, Actogenix. Steidler, L.: Employee, Actogenix, Stockholder, Actogenix.

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