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J Thorac Cardiovasc Surg 1998;115:998-1002
© 1998 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

Triple immunosuppression reduces mononuclear cell infiltration andprolongs graft life in pig–to–newborn baboon cardiacxenotransplantation

Supported in part by a gift from Roche Pharmaceuticals.

Read in part at the Seventeenth Annual Meeting of the InternationalSociety of Heart and Lung Transplantation, London, United Kingdom, April 3-6,1997.

Received for publication April 22, 1997. Revisions requested August 11, 1997. Accepted for publication Dec. 5, 1997. Address for reprints: Robert E. Michler, MD, Karl P. Klassen Professorof Surgery, Chief, Division of Cardiothoracic Surgery, Doan Hall North, OhioState University Medical Center, 410 West 10th Ave., Columbus, OH 43210.

Abstract

Objective: Pig hearts transplanted intounmedicated newborn baboons do not undergo hyperacute rejection by preformedxenoantibody and complement. These grafts are rejected at days 3 to 4 inassociation with the infiltration of macrophages and natural killer cells. Weinvestigated whether an immunosuppressive regimen used widely in cardiacallotransplantation could reduce this cellular response and prolong xenograftlife.
Methods: Ten newborn baboonsunderwent heterotopic pig cardiac xenotransplantation. Five baboons wereimmunosuppressed with mycophenolate mofetil (100 mg/kg), methylprednisoloneacetate (0.8 mg/kg), and cyclosporine A (INN: ciclosporin; 10 mg/kg). Xenograftrejection was studied by light microscopy and immunofluorescence. The inducedhumoral response to porcine xenoantigens was documented by enzyme-linkedimmunosorbent assay using synthetic -1,3-galactosyl epitopes coupled tobovine serum albumin.
Results: Graft lifewas extended from a mean of 3.6 ± 0.5 days (n =5) to a mean of 6.2  ± 1.1 days (n =5, p = 0.01). In comparison with controls,explanted grafts from medicated baboons demonstrated reduced infiltration withnatural killer cells and macrophages, but increased evidence ofcomplement-mediated rejection substantiated by increased deposition ofimmunoglobulin M, complement, and fibrin. In all baboons receiving transplants,levels of both immunoglobulin M and immunoglobulin G anti-galactose weresignificantly increased after transplantation, with immunoglobulin G levelsremaining persistently elevated.
Conclusions:These results indicate that cyclosporine-based triple immunosuppressionmarginally prolonged xenograft survival and appears to have reduced the naturalkiller cell and macrophage infiltrates. The immunosuppressive protocol, however,was not adequate to prevent the induced immunoglobulin M humoral response andprevent complement-mediated graft injury. (J Thorac Cardiovasc Surg1998;115:998-1006)

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