title: Administration of a negative vaccination induces hyporesponsiveness to islet allografts.
abstract: As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund's Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant.
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Sklavos
authors.forename: G M
authors.initials: GM
authors.lastname: Coudriet
authors.forename: M
authors.initials: M
authors.lastname: Delmastro
authors.forename: S
authors.initials: S
authors.lastname: Bertera
authors.forename: J T
authors.initials: JT
authors.lastname: Coneybeer
authors.forename: J
authors.initials: J
authors.lastname: He
authors.forename: M
authors.initials: M
authors.lastname: Trucco
authors.forename: J D
authors.initials: JD
authors.lastname: Piganelli
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005620:Freund's Adjuvant / Q000276:immunology / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008055:Lipids / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000187:drug effects / Q000528:radiation effects; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; C114843:incomplete Freund's adjuvant; D016753:Interleukin-10; D007371:Interferon-gamma; D005620:Freund's Adjuvant