title: New concepts of immune modulation in xenotransplantation.
abstract: The shortage of human organs for transplantation has focused research on the possibility of transplanting pig organs into humans. Many factors contribute to the failure of a pig organ graft in a primate. A rapid innate immune response (natural anti-pig antibody, complement activation, and an innate cellular response; e.g., neutrophils, monocytes, macrophages, and natural killer cells) is followed by an adaptive immune response, although T-cell infiltration of the graft has rarely been reported. Other factors (e.g., coagulation dysregulation and inflammation) appear to play a significantly greater role than in allotransplantation. The immune responses to a pig xenograft cannot therefore be controlled simply by suppression of T-cell activity. Before xenotransplantation can be introduced successfully into the clinic, the problems of the innate, coagulopathic, and inflammatory responses will have to be overcome, most likely by the transplantation of organs from genetically engineered pigs. Many of the genetic manipulations aimed at protecting against these responses also reduce the adaptive response. The T-cell and elicited antibody responses can be prevented by the biological and/or pharmacologic agents currently available, in particular, by costimulation blockade-based regimens. The exogenous immunosuppressive regimen may be significantly reduced by the presence of a graft from a pig transgenic for a mutant (human) class II transactivator gene, resulting in down-regulation of swine leukocyte antigen class II expression, or from a pig with "local" vascular endothelial cell expression of an immunosuppressive gene (e.g., CTLA4-Ig). The immunomodulatory efficacy of regulatory T cells or mesenchymal stromal cells has been demonstrated in vitro but not yet in vivo.
authors.affiliation: 1 Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA. 2 Revivicor, Blacksburg, VA. 3 Address correspondence to: David K.C. Cooper, M.D., Ph.D., F.R.C.S., Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Biomedical Science Tower, W1543, 200 Lothrop Street, Pittsburgh, PA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Satyananda
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: Mohamed B
authors.initials: MB
authors.lastname: Ezzelarab
authors.forename: Carol
authors.initials: C
authors.lastname: Phelps
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D015316:Genetic Therapy; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D011323:Primates; D013552:Swine / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014019:Tissue Donors / Q000600:supply & distribution*; D023001:Transplantation Tolerance / Q000235:genetics; D014183:Transplantation, Heterologous / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents