Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity.
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.
Abedi
M
M
Department of Research, Roger Williams Medical Center, Providence, RI 02908, USA.
Greer
D
D
Lambert
J F
JF
Colvin
G A
GA
Dooner
M S
MS
McAuliffe
C I
CI
Demers
D
D
Moore
B E
BE
Quesenberry
P J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000276:immunology*; D017690:Cell Transplantation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D014644:Genetic Variation; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D013154:Spleen / Q000166:cytology; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D023201:CD40 Ligand