High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response

L. Bühler, M. Awwad, M. Basker, S. Gojo, A. Watts, S. Treter, K. Nash, G. Oravec, Q. Chang, A. Thall, J. D. Down, M. Sykes, D. Andrews, R. Sackstein, M. E. White-Scharf, D. H. Sachs, D. K.C. Cooper

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140 Scopus citations

Abstract

Background: In pig-to-primate organ transplantation, hyperacute rejection can be prevented, but the organ is rejected within days by acute vascular rejection, in which induced high-affinity anti-Galα1-3Gal (αGal) IgG and possibly antibodies directed against new porcine (non-αGal) antigenic determinants are considered to play a major role. We have explored the role of an anti-CD40L monoclonal antibody in modifying the humoral response to porcine hematopoietic cells in baboons pretreated with a nonmyeloablative regimen. Methods: Porcine peripheral blood mobilized progenitor cells obtained by leukapheresis from both major histocompatibility complex-inbred miniature swine (n=7) and human decay-accelerating factor pigs (n=3) were transplanted into baboons. Group 1 baboons (n=3) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with ATG, complement depletion with cobra venom factor, short courses of cyclosporine, mycophenolate mofetil, porcine hematopoietic growth factors, and anti-αGal antibody depletion by immunoadsorption before transplantation of high doses (2-4x1010/cells/kg) of peripheral blood mobilized progenitor cells. In group 2 (n=5), cyclosporine was replaced by eight doses of anti-CD40L monoclonal antibodies over 14 days. The group 3 baboons (n=2) received the group 1 regimen plus 2 doses of anti-CD40L monoclonal antibodies (on days 0 and 2). Results: In group 1, sensitization to αGal (with increases in IgM and IgG of 3- to 6-fold and 100-fold, respectively) and the development of antibodies to new non-αGal porcine antigens occurred within 20 days. In group 2, no sensitization to αGal or non-αGal determinants was seen, but αGal-reactive antibodies did return to their pre- peripheral blood mobilized progenitor cells transplant levels. In group 3, attenuated sensitization to αGal antigens was seen after cessation of cyclosporine and mycophenolate mofetil therapy at 30 days (IgM 4-fold, IgG 8-30-fold), but no antibodies developed against new porcine determinants. In no baboon did anti-CD40L monoclonal antibodies prevent sensitization to its own murine antigens. Conclusions: We believe that the studies are the first to consistently demonstrate prevention of a secondary humoral response after cell or organ transplantation in a pig-to-primate model. The development of sensitization to the murine elements of the anti-CD40L monoclonal anti bodies suggests that nonresponsiveness to cell membrane-bound antigen (e.g.,αGal) is a specific phenomenon and not a not a general manifestation of immunological unresponsiveness. T cell costimulatory blockade may facilitate induction of mixed hematopoietic chimerism and, consequently, of tolerance to pig organs and tissues.

Original languageEnglish (US)
Pages (from-to)2296-2304
Number of pages9
JournalTransplantation
Volume69
Issue number11
DOIs
StatePublished - Jun 15 2000
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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