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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2175-2182
Allogeneic hematopoietic chimerism in mice treated with
sublethal myeloablation and anti-CD154 antibody: absence of
graft-versus-host disease, induction of skin allograft tolerance, and
prevention of recurrent autoimmunity in islet-allografted NOD/Lt
mice
Edward Seung,
Neal Iwakoshi,
Bruce A. Woda,
Thomas G. Markees,
John P. Mordes,
Aldo A. Rossini, and
Dale L. Greiner
From the Program in Immunology and Virology and Program in Molecular
Medicine, Departments of Medicine and Pathology, University of
Massachusetts Medical School, Worcester, MA.
We describe a tolerance-based stem cell transplantation protocol
that combines sublethal radiation with transient blockade of the
CD40-CD154 costimulatory pathway using an anti-CD154 antibody. With
this protocol, we established hematopoietic chimerism in BALB/c mice
transplanted with fully allogeneic C57BL/6 bone marrow. The percentage
of donor-origin mononuclear cells in recipients was more than 99%. In
addition, all chimeric mice treated with anti-CD154 antibody remained
free of graft-versus-host disease (GVHD) and accepted donor-origin but
not third-party skin allografts. It was similarly possible to create
allogeneic hematopoietic chimerism in NOD/Lt mice with spontaneous
autoimmune diabetes. Pancreatic islet allografts transplanted into
chimeric NOD/Lt mice were resistant not only to allorejection but also
to recurrence of autoimmunity. We conclude that it is possible to
establish robust allogeneic hematopoietic chimerism in sublethally
irradiated mice without subsequent GVHD by blocking the CD40-CD154
costimulatory pathway using as few as 2 injections of anti-CD154
antibody. We also conclude that chimerism created in this way generates
donor-specific allograft tolerance and reverses the predisposition to
recurrent autoimmune diabetes in NOD/Lt mice, enabling them to accept
curative islet allografts.
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