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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2750-2757
IMMUNOBIOLOGY
Long-term induction of immune tolerance after blockade of
CD40-CD40L interaction in a mouse model of hemophilia A
Gabriela Rossi,
Jolly Sarkar, and
Dorothea Scandella
From the Department of Immunology, Holland Laboratory,
American Red Cross, Rockville, MD.
A factor VIII-deficient knockout mouse was used as a model for
severe hemophilia A to characterize the immune response to recombinant
human factor VIII (fVIII) and to study new approaches for induction of
immune tolerance to fVIII. Mice initially received periodic injections
of fVIII in doses similar to those used for the treatment of human
hemophilia A. To induce immune tolerance, a hamster monoclonal antibody
specific for murine CD40 ligand (CD40L or CD154) was injected with
fVIII. Control mice received fVIII alone or fVIII and hamster
immunoglobulin G. After treatment, humoral and cellular immune
responses were evaluated. Ninety-five percent of anti-CD40L-treated
mice had lower titers of anti-fVIII antibody (less than 1 µg/mL)
compared with fVIII-injected control mice (mean, 18 µg/mL). To
determine whether anti-CD40L treatment induces long-term immune
tolerance, mice were rechallenged 3 times with fVIII alone. At 150 days
after treatment, 12 of 22 anti-CD40L-treated mice remained tolerant to
fVIII (anti-fVIII antibody titers less than 1 µg/mL). However,
tolerant mice immunized with tetanus toxoid (TT) developed high anti-TT
antibody, demonstrating that tolerance is fVIII specific. T cells from
tolerant mice showed impaired proliferative responses after stimulation
with fVIII in vitro and lack of production of the cytokines
interleukin-2 (IL-2), IL-4, interferon  , and IL-10. These results
demonstrate that long-term immune tolerance to fVIII was effectively
induced after early blockade of CD40-CD40L interaction. In addition,
the lack of tolerance in this model was associated with the expression of a Th2 phenotype.
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