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Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity

Leukemia volume 17, pages 1871–1879 (2003)Cite this article

Abstract

Long-term multilineage allochimerism can be obtained in H2-mismatched B6.SJL to BALB/c transplants with host irradiation of 100 cGy, donor spleen cell pre-exposure and costimulator blockade with anti-CD40 ligand (CD40L) antibody. We evaluated this allochimerism approach in murine marrow transplants with different degrees of major histocompatibility complexe (MHC) mismatching; these include: (1) H2-mismatched transplant H2Kk to H2Kb, (2) full haplo-identical transplant H2Kbd to H2Kbk, (3) a partial haplo-identical transplant H2Kd to H2Kbd and (4) an MHC class II mismatch. Levels of chimerism increased up to 12 weeks and then stayed relatively stable up to 1 year after transplant. At 18 weeks post-transplant, the H2-mismatched, haplo-identical, partial haplo-identical and class II-mismatch transplants evidenced 17.9±4.4, 40.7±0.9, 25.1±4.19 and 33.7±3.5% donor chimerism, respectively. Dropping the anti-CD40 antibody treatment and spleen cells or changing the schedule of antibody to one injection, in haplo-identical or full-mismatched transplants resulted in no donor-derived chimerism. On the other hand, these still resulted in minor chimerism in class II-mismatched transplants. Lineage analysis of peripheral blood at 6 and 12 months post-transplant demonstrated a significant shift toward increased chimeric lymphocytes and decreased chimeric granulocytes in the full H2 as compared with haplo-identical or class II transplants. Transplantation with anti-CD40L antibody eliminated both graft-versus-leukemia and graft-versus-host disease (GVHD) and delayed lymphocyte infusion did not rescue animals from fatal leukemia. In conclusion, under the conditions of our tolerization regimen, a haplo transplant gives higher engraftment levels than a full H2 mismatch, and despite lower engraftment levels, a class II-mismatched transplant can be successfully accomplished with only 100 cGy and no CD40L blockade.

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Authors and Affiliations

  1. Department of Research, Roger Williams Medical Center, Providence, RI, USA

    M Abedi, D Greer, J F Lambert, G A Colvin, M S Dooner, C I McAuliffe, D Demers, B E Moore & P J Quesenberry

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  1. M Abedi
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  2. D Greer
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  3. J F Lambert
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  4. G A Colvin
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This work was supported by Grants P01-HL-56920, PO1-DK-5022, RO1-DK-49650, R01-DK2742.

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Abedi, M., Greer, D., Lambert, J. et al. Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity. Leukemia 17, 1871–1879 (2003). https://doi.org/10.1038/sj.leu.2403070

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