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Earlier Low‐Dose TBI or DST Overcomes CD8 + T‐Cell‐Mediated Alloresistance to Allogeneic Marrow in Recipients of Anti‐CD40L
Author(s) -
Takeuchi Yasuo,
Ito Hiroshi,
Kurtz Josef,
Wekerle Thomas,
Ho Leon,
Sykes Megan
Publication year - 2004
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1046/j.1600-6135.2003.00272.x
Subject(s) - cd8 , medicine , cd154 , total body irradiation , immunology , immune tolerance , t cell , bone marrow , cytotoxic t cell , haematopoiesis , monoclonal antibody , cd40 , antibody , immune system , stem cell , chemotherapy , biology , in vitro , microbiology and biotechnology , cyclophosphamide , biochemistry
Treatment with a single injection of anti‐CD40L (CD154) monoclonal antibody (mAb) and fully mismatched allogeneic bone marrow transplant (BMT) allows rapid tolerization of CD4 + T cells to the donor. The addition of in vivo CD8 T‐cell depletion leads to permanent mixed hematopoietic chimerism and tolerance. We now describe two approaches that obviate the requirement for CD8 T‐cell depletion by rapidly tolerizing recipient CD8 T cells in addition to CD4 cells. Administration of donor‐specific transfusion (DST) to mice receiving 3 Gy total body irradiation (TBI), BMT and anti‐CD40L mAb on day 0 uniformly led to permanent mixed chimerism and tolerance, compared with only 40% of mice receiving similar treatment without DST. In the absence of DST, moving the timing of 3 Gy TBI to day –1 or day –2 instead of day 0 led to rapid (by 2 weeks) induction of CD8 + cell tolerance, and also permitted uniform achievement of permanent mixed chimerism and donor‐specific tolerance in recipients of anti‐CD40L and BMT on day 0. These nontoxic regimens overcome CD8 + and CD4 + T‐cell‐mediated alloresistance without requiring host T‐cell depletion, permitting the induction of permanent mixed chimerism and tolerance .