title: Organ donor or graft pretreatment to prolong allograft survival: lessons learned in the murine model.
abstract: Permanent donor-specific tolerance to allografts is the goal of transplantation research. Currently, morbid immunosuppressive therapy is used to mitigate rejection initiated in part by Ia-bearing interstitial graft dendritic or antigen-presenting cells (APCs) that are thought to migrate into the host after transplantation. We hypothesized that donor or organ immune modulation directed against graft APCs might influence graft immunogenicity and promote prolonged graft acceptance in histoincompatible hosts in the absence of immunosuppressive therapy. Haplotype-specific monoclonal antibodies (mAb), mAb specific to graft APC, adhesion or costimulatory molecules and anti-LFA-1-Ricin and anti-Iak-Ricin immunoconjugates (IC) were prepared and administered in varying doses and time intervals to donor C3H/HeJ (H-2k) mice. Thereafter, their spleens and hearts were removed at varying time intervals and used either as stimulator cells in one-way mixed lymphocyte reaction or transplanted into naive Balb/c (H-2d) recipients, respectively. Explanted C3H hearts were pretreated with anti-Iak mAb on the Langendorf apparatus. Hearts were also used from major histocompatibility complex (MHC) class I, MHC class II, and MHC class I- and II-deficient "knockout" mice. Splenocytes exposed to at least 500 microg of anti-Iak mAb in vivo for more than 4 hr were able to inhibit the mixed lymphocyte reaction to almost background levels, but only after incubation with rabbit complement in vitro. Similarly pretreated cardiac allografts (both in vivo or explanted and pretreated on the Langendorf apparatus) did not experience prolonged survival in nonimmunosuppressed Balb/C recipients when compared with control solutions, regardless of the concomitant use of complement. Splenocytes from immunoconjugate pretreated donors inhibited the mixed lymphocyte reaction completely without the use of complement; however, hearts from these donors also did not experience prolonged survival nor donor hearts exposed to mAb specific for graft APC, adhesion or costimulatory molecules. Only hearts from MHC class I and class II "knockout" mice survived significantly longer than controls. We conclude that donor or graft pretreatment with haplotype-specific anti-Ia mAb, haplotype-specific immunoconjugates, or mAb directed against graft APC, adhesion or costimulation molecules have little efficacy in promoting acceptance of cardiac allografts in nonimmunosuppressed recipients. The enhanced survival of hearts from MHC class I- and class II-deficient donors suggest that novel methods to effect the immunogenicity of the graft will be required if long-term allograft acceptance is to be achieved in the absence of host immunosuppression.
authors.affiliation: Department of Surgery, University of Illinois at Chicago, 60612, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pollak
authors.forename: J M
authors.initials: JM
authors.lastname: Blanchard
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000276:immunology; D005260:Female; D006085:Graft Survival / Q000502:physiology*; D006649:Histocompatibility Antigens / Q000235:genetics; D018796:Immunoconjugates / Q000276:immunology / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL / Q000235:genetics; D018345:Mice, Knockout / Q000235:genetics; D011817:Rabbits; D013997:Time Factors; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D006649:Histocompatibility Antigens; D018796:Immunoconjugates; D001613:beta 2-Microglobulin; D018799:Intercellular Adhesion Molecule-1