title: Differential Role of B Cells and IL-17 Versus IFN-γ During Early and Late Rejection of Pig Islet Xenografts in Mice.
abstract: Xenogeneic islet transplantation is an emerging therapeutic option for diabetic patients. However, immunological tolerance to xenogeneic islets remains a challenge.
  
  
  
  The current study used a pig-to-mouse discordant xenogeneic islet transplant model to examine antidonor xenogeneic immune responses during early and late rejection and to determine experimental therapeutic interventions that promote durable pig islet xenograft survival.
  
  
  
  We found that during early acute rejection of pig islet xenografts, the rejecting hosts exhibited a heavy graft infiltration with B220 B cells and a robust antipig antibody production. In addition, early donor-stimulated IL-17 production, but not IFN-γ production, dominated during early acute rejection. Recipient treatment with donor apoptotic 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide-treated splenocytes significantly inhibited antidonor IL-17 response, and when combined with B cell depletion and a short course of rapamycin led to survival of pig islet xenografts beyond 100 days in approximately 65% recipients. Interestingly, treated recipients in this model experienced late rejection between 100 and 200 days posttransplant, which coincided with B cell reconstitution and an ensuing emergence of a robust antidonor IFN-γ, but not IL-17, response.
  
  
  
  These findings reveal that early and late rejection of pig islet xenografts may be dominated by different immune responses and that maintenance of long-term xenogeneic tolerance will require strategies that target the temporal sequence of antixenogeneic immune responses.
authors.affiliation: 1 Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL. 2 Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China. 3 Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL. 4 Department of Surgery, University of Minnesota, Schulze Diabetes Institute, Minneapolis, MN. 5 Division of Endocrinology, First Affiliated Hospital of Guangzhou Medical University, Guangdong, China. 6 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL. 7 Department of Microbiology and Immunology, Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Hee Kap
authors.initials: HK
authors.lastname: Kang
authors.forename: Shusen
authors.initials: S
authors.lastname: Wang
authors.forename: Anil
authors.initials: A
authors.lastname: Dangi
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Amar
authors.initials: A
authors.lastname: Singh
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: James M
authors.initials: JM
authors.lastname: Rosati
authors.forename: Wilma
authors.initials: W
authors.lastname: Suarez-Pinzon
authors.forename: Xuelian
authors.initials: X
authors.lastname: Deng
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D064593:Heterografts; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
chemical_list: D020381:Interleukin-17; D007371:Interferon-gamma