New strategy for allotransplantation
Authors: Richard D Granstein
Journal: The Lancet (1996)

Effective use of immunosuppression to prevent the immunological rejection of transplanted organs underlies the success of allotransplantation. Nonetheless, long-term immunosuppression is associated with adverse effects such as renal toxicity, hypertension, diabetes, and development of malignancies. Moreover, chronic vascular rejection remains a cause of transplant failure. Thus new approaches to allotransplantation remain welcome. Larsen and collaborators have lately described the effect of blockade of CD28-B7 interactions and CD40-gp39 interactions on cardiac and skin allograft survival.1Larsen CP Elwood ET Alexander DZ et al.Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.Nature. 1996; 381: 434-438Crossref PubMed Scopus (1272) Google Scholar Effective T-cell activation seems to require two signals.2Mondino A Jenkins MK Surface proteins involved in T cell costimulation.J Leukoc Biol. 1994; 55: 805-815PubMed Google Scholar One is mediated by engagement of the T-cell-receptor complex (TCR) with major histocompatibility complex class I or class II antigens containing an antigenic peptide. Considerable evidence suggests that interaction of the CD28 molecule on T cells with a member(s) of the B7 family of counter-receptors can provide the second (“co-stimulatory”) signal for T-cell activation. Blockade of this pathway prolongs allograft survival in several models and can result in the induction of tolerance when combined with additional manoeuvres.3Pearson TC Alexander DZ Hendrix R et al.CTLA4-Ig plus bone marrow induces long-term allograft survival and donor-specific unresponsiveness in the murine model.Transplantation. 1996; 61: 997-1004Crossref PubMed Scopus (116) Google Scholar, 4Lenshow DJ Zeng Y Hathcock KS et al.Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies.Transplantation. 1995; 60: 1171-1178Crossref PubMed Scopus (151) Google Scholar Nonetheless, blockade of this pathway alone seems to be insufficient for reliable engraftment of highly immunogenic allografts.5Turka LA Linsley PS Lin H et al.T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo.Proc Natl Acad Sci USA. 1992; 89: 11102-11105Crossref PubMed Scopus (539) Google Scholar The CD40-gp39 pathway is important for B-cell activation, isotype switching, and various forms of T-cell help for B cells.6Foy TM Durie FH Noelle RJ The expansive role of CD40 and its ligant gp39, in immunity.Sem Immunol. 1994; 6: 259-266Crossref PubMed Scopus (37) Google Scholar, 7Durie FH Foy TM Masters SR et al.The role of CD40 in the regulation of humoral and cell-mediated immunity.Immunol Today. 1994; 15: 406-411Summary Full Text PDF PubMed Scopus (347) Google Scholar There is also evidence that an interaction between CD40 and gp39 plays a part in T-cell activation, and blockade of this pathway in some systems may lead to T-cell tolerance7Durie FH Foy TM Masters SR et al.The role of CD40 in the regulation of humoral and cell-mediated immunity.Immunol Today. 1994; 15: 406-411Summary Full Text PDF PubMed Scopus (347) Google Scholar, 8Cayabyab M Phillips JH Lanier LL CD40 preferentially costimulates activation of CD4+ T lymphocytes.J Immunol. 1994; 152: 1523-1531PubMed Google Scholar, 9Parker DC Greiner DL Phillips NE et al.Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand.Proc Natl Acad Sci USA. 1995; 92: 9560-9564Crossref PubMed Scopus (382) Google Scholar, 10Larsen CP Alexander DZ Hollenbaugh D et al.CD40-gp39 interactions play a critical role during allograft rejection by blockade of the CD40-gp39 pathway.Transplantation. 1996; 61: 4-9Crossref PubMed Scopus (304) Google Scholar as well as prolonged survival of allografts in some models.9Parker DC Greiner DL Phillips NE et al.Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand.Proc Natl Acad Sci USA. 1995; 92: 9560-9564Crossref PubMed Scopus (382) Google Scholar, 10Larsen CP Alexander DZ Hollenbaugh D et al.CD40-gp39 interactions play a critical role during allograft rejection by blockade of the CD40-gp39 pathway.Transplantation. 1996; 61: 4-9Crossref PubMed Scopus (304) Google Scholar However, blockade of the CD40-gp39 pathway alone also does not appear sufficient to reliably permit permanent engraftment of highly immunogenic allografts. Experiments examining interruption of both pathways could thus be of interest. Larsen and collaborators used a model in which C3H/J mice (H-2k) received BALB/c (H-2d) hearts. Recipients were treated with CTLA4-Ig (an immunoglobulin fusion protein that binds to the ligands for CD28 and its homologue CTLA-4) and/or the anti-gp39 antibody MR1. Either treatment alone significantly prolonged graft survival. However, the combination produced a much greater effect, with all hearts surviving to the end of the study at 80 days. In CTLA4-Ig-treated animals histological examination of cardiac allografts showed extensive lymphocytic infiltration, interstitial fibrosis, and severe coronary arterial intimal thickening and fibrosis consistent with chronic rejection. These features were less severe in MR1-treated animals. They were absent in grafts from animals treated with both modalities. Of particular importance was an additional experiment in which BALB/c skin grafts were transplanted onto recipient C3H/J. Again, the rate of allograft survival was much greater (mean survival >50 days) with MR1 plus CTLA4-Ig than with either treatment alone—graft survival in mice treated with CTLA4-Ig alone, MR1 alone, or cyclosporin, or an anti-CD4 monoclonal antibody was unchanged compared with that in untreated controls. These results are striking because cutaneous allografts are highly immunogenic and are generally rejected faster than vascularised organ allografts.13 This difference might be due to the extensive non-specific inflammation caused by damage to the dermis and the amount of ischaemic necrosis in the post-graft period since the vasculature of the skin is not anastomosed to that of the host.11Unanue ER Benecerraf B Textbook of immunology. Williams and Wilkins, Baltimore1984Google Scholar The success of simultaneous blockage of the CD28-B7 and CD40-gp39 pathways in preventing rejection of cardiac and cutaneous allografts appears impressive. The mechanism(s) of the long-term tolerance remains unknown. Induction of anergy by TCR engagement in the absence of co-stimulation12Schwatz RH Models of T cell anergy: is there a common molecular mechanism?.J Exp Med. 1996; 184: 1-8Crossref PubMed Scopus (454) Google Scholar could be involved here. Of course, much work remains to be done in the laboratory before applying these findings in the clinic. One must also remain sceptical because many techniques that are successful in animal models are not so in human beings. Nonetheless, with these impressive results, inhibition of these two pathways may be a responsible strategy to pursue for exploring the long-term acceptance of clinical allografts with the potential for diminished side-effects.