title: Cellular participation in delayed xenograft rejection of hCD55 transgenic pig hearts by baboons.
abstract: Delayed xenograft rejection (DXR) of pig organs by baboons currently represents the major obstacle to successful xenotransplantation. Although antibodies (Abs) are believed to play a fundamental role in this form of rejection, so far little is known concerning the potential cellular component. Biopsies taken during DXR of human CD55 transgenic pig hearts by non-treated (n = 2), alpha-Gal immunoadsorbed (n = 2), or immunosuppressed (n = 9) baboons were studied. The cellular element was explored by determining not only its phenotype by classical immunohistochemical techniques but also its activity in terms of cytokines, cytolytic enzymes and other mediators using quantitative reverse transcription polymerase chain reaction. All porcine xenografts underwent DXR; within 5 days in non-treated and immunoadsorbed animals but significantly delayed (6 to 29 days) in immunosuppressed animals. Cellular infiltration in non-immunosuppressed grafts consisted predominantly of monocytes/macrophages, CD8 cells and a few CD4 T-cells. The predominant baboon transcripts detectable were the proinflammatory cytokines interleukin1-alpha and tumor necrosis factor-alpha, the lymphokine interferon-gamma and the cytotoxic enzyme granzyme B. However, these cellular components were lacking in the immunosuppressed animals. Despite these differences, strong immunoglobulin M (IgM) and C5b-9 complement deposition was observed in all animals at rejection. Together our findings suggest that although the humoral response plays a predominant role in DXR through IgM Abs and complement activation, there is a clear cellular infiltrate in DXR in this model that is likely to contribute to rejection through a strong pro-inflammatory and cytotoxic environment, necessitating substantial immunosuppression for a prolonged graft survival.
authors.affiliation: INSERM U437, Immunointervention in allo and xenotransplantation, and ITERT, Institut de Transplantation et de Recherche en Transplantation, Nantes, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ashton-Chess
authors.forename: Jean-Christian
authors.initials: JC
authors.lastname: Roussel
authors.forename: Rafael
authors.initials: R
authors.lastname: Manez
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cozzi
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics; D001483:Base Sequence; D018958:CD55 Antigens / Q000032:analysis / Q000235:genetics*; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007163:Immunosorbent Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D010215:Papio; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000910:Antibodies, Heterophile; D015703:Antigens, CD; D018958:CD55 Antigens; D016207:Cytokines; D017931:DNA Primers; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D007041:Hypoxanthine Phosphoribosyltransferase