Abstract
Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vbeta11(+) T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening ("chronic rejection").
Highlights
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We show that combinations of anti-LFA-1 with anti-CD40 ligand (CD40L) or the rapamycin derivative everolimus (40-O-(2-hydroxyethyl)-rapamycin) [23] induce stable, mixed hemopoietic chimerism upon transfer of a single standard dose of allogeneic bone marrow (BM) cells (2 ϫ 107), and irradiation-free conditioning with the alkylating agent busulfan for partial depletion of early hemopoietic stem cells [13, 24]
We describe novel combinations of antiLFA-1 with anti-CD40L and everolimus that support the development of stable, mixed hemopoietic chimerism and transplantation tolerance after fully allogeneic BMTx
Summary
We further confirmed that lack of alloantibody formation correlated with transient mixed chimerism and was not achieved by anti-LFA-1 plus everolimus alone, because all anti-LFA-1 plus everolimus-treated recipients of syngeneic B6 BM and BALB/c skin acutely rejected their skin grafts with the same moderate delay (median, day 17; Table III, group 5), yet displayed high levels of IgG (mean fluorescence intensity 169, Table III, group 5).
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