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Received 19 July 1999.
Accepted 22 December 1999.
0041-1337/00/6911-2296/0
TRANSPLANTATION Vol. 69, 2296 –2304, No. 11, June 15, 2000
Copyright © 2000 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A.
HIGH-DOSE PORCINE HEMATOPOIETIC CELL
TRANSPLANTATION COMBINED WITH CD40 LIGAND BLOCKADE
IN BABOONS PREVENTS AN INDUCED ANTI-PIG HUMORAL
RESPONSE
L. B
¨
UHLER,
1
M. AWWAD,
4
M. BASKER,
1
S. GOJO,
1
A. WATTS,
4
S. TRETER,
4
K. NASH,
1
G. ORAVEC,
1
Q. CHANG,
4
A. THALL,
4
J. D. DOWN,
4
M. SYKES,
1
D. ANDREWS,
2
R. SACKSTEIN,
3
M. E. WHITE-SCHARF,
4
D. H. SACHS,
1
AND D. K. C. COOPER
1,5
Transplantation Biology Research Center, and Departments of Pathology and Medicine,
Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129 and BioTransplant Inc.,
Charlestown, MA 02129
Background. In pig-to-primate organ transplanta-
tion, hyperacute rejection can be prevented, but the
organ is rejected within days by acute vascular rejec-
tion, in which induced high-affinity anti-Gal1–3Gal
(Gal) IgG and possibly antibodies directed against
new porcine (non-Gal) antigenic determinants are
considered to play a major role. We have explored the
role of an anti-CD40L monoclonal antibody in modify-
ing the humoral response to porcine hematopoietic
cells in baboons pretreated with a nonmyeloablative
regimen.
Methods. Porcine peripheral blood mobilized pro-
genitor cells obtained by leukapheresis from both ma-
jor histocompatibility complex-inbred miniature
swine (n7) and human decay-accelerating factor pigs
(n3) were transplanted into baboons. Group 1 ba-
boons (n3) underwent whole body (300 cGy) and thy-
mic (700 cGy) irradiation, T cell depletion with ATG,
complement depletion with cobra venom factor, short
courses of cyclosporine, mycophenolate mofetil, por-
cine hematopoietic growth factors, and anti-Gal an-
tibody depletion by immunoadsorption before trans-
plantation of high doses (2– 410
10
/cells/kg) of
peripheral blood mobilized progenitor cells. In group
2 (n5), cyclosporine was replaced by eight doses of
anti-CD40L monoclonal antibodies over 14 days. The
group 3 baboons (n2) received the group 1 regimen
plus 2 doses of anti-CD40L monoclonal antibodies (on
days 0 and 2).
Results. In group 1, sensitization to Gal (with in-
creases in IgM and IgG of 3- to 6-fold and 100-fold,
respectively) and the development of antibodies to
new non-Gal porcine antigens occurred within 20
days. In group 2, no sensitization to Gal or non-Gal
determinants was seen, but Gal-reactive antibodies
did return to their pre- peripheral blood mobilized
progenitor cells transplant levels. In group 3, attenu-
ated sensitization to Gal antigens was seen after ces-
sation of cyclosporine and mycophenolate mofetil
therapy at 30 days (IgM 4-fold, IgG 8 –30-fold), but no
antibodies developed against new porcine determi-
nants. In no baboon did anti-CD40L monoclonal anti-
bodies prevent sensitization to its own murine anti-
gens.
1
Transplantation Biology Research Center.
2
Department of Pathology.
3
Department of Medicine.
4
Biotransplant Inc.
5
Address correspondence to: D. K. C. Cooper, MD, PhD, FRCS,
Transplantation Biology Research Center, Massachusetts General
Hospital, MGH East, Building 149-9019, 13th Street, Boston, MA
02129.
TRANSPLANTATION 2296 Vol. 69, No. 11