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

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 17.974.4, 40.770.9, 25.174.19 and 33.773.5% donor chimerism, respectively. Dropping the anti-CD40 antibody treatment and spleen cells or changing the schedule of antibody to one injection, in haploidentical or full-mismatched transplants resulted in no donorderived 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 graftversus-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.

Perspective: fundamental and clinical concepts on stem cell homing and engraftment: a journey to niches and beyond

“…Manipulation of the dose and schedule of marrow infusions has allowed us to drop the irradiation altogether [103]. Further work has shown, not surprisingly, that lesser degrees of H2 incompatibility resulted in improved alloengraftment results [104].…”

Low Dose Total Body Irradiation Followed by Allogeneic Lymphocyte Infusion for Refractory Hematologic Malignancy—an Updated Review

“…Interestingly, when 200 million cells were infused at time 0, there was essentially no engraftment, so that scheduling was a critical component of engraftment. Most recently, we have shown that with lesser degrees of H-2 histoincompatibility there are higher levels of engraftment [9].…”