HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection.

Donor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible "permissive" mismatches, we examined the relationship between direction of human leukocyte antigen mismatch ("vector") and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.

Combined neonatal blood transplants in a parent-to-F1 mouse model: improved survival rates and stable long-term engraftment.

The use of cord blood (CB) transplantation for adult patients is limited by the relatively low cell content of a single collection. Two, partially-matched CB grafts could provide optimal cell doses. The interactions among the donor-derived populations have not been fully evaluated. We used our mouse model (Neonatal peripheral blood--NPB--transplants to adult recipients) to evaluate whether grafts from two histocompatibility-disparate donors ("combined" grafts) had higher survival and faster hematopoietic recovery than single donor transplants, each at suboptimal cell dose (leading to survival <60%). Transplants were performed in a parent-to-F1 setting: NPB or bone marrow (BM) cells from the fully mismatched, homozygous parental strains (A/J, B6) were given to myeloablated B6AF1 recipients. Outcomes improved by combining NPB grafts: 48% of A/J graft recipients (1 x 10(6) cells/animal) survived; all animals transplanted with B6 (same cell dose) died. Survival after combined NPB transplants was 75% (P < 0.01) and recipients had accelerated recovery of WBCs and platelets compared to single donor A/J grafts (P < 0.01). No such improvements occurred with suboptimal dose combined BM transplants. Recipients of combined NPB grafts reconstituted with one donor primarily. Chimerism levels remained stable. Successful secondary transplants demonstrated long-term persistence of both NPB grafts. Combined haplo-identical NPB but not BM grafts, each transplanted at suboptimal cell doses, engraft synergistically leading to faster reconstitution. Although the mouse model does not fully represent the complex clinical aspects of human transplantation, our findings support the concept of using two CB grafts for adult patients when a sufficiently large single one is not available.

Complement receptor 1 inhibitors for prevention of immune-mediated red cell destruction: potential use in transfusion therapy.

Activation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell (RBC) destruction, causing transfusion reactions and hemolytic anemia. In the present study, we have assessed the ability of a human recombinant soluble form of complement receptor 1 (sCR1) to inhibit complement-mediated RBC destruction in vitro and in vivo. Using an in vitro alloimmune incompatibility model, sCR1 inhibited complement activation and prevented hemolysis. Following transfusion of human group O RBCs into mice lacking detectable pre-existing antibodies against the transfused RBCs, systemic coadministration of 10 mg/kg sCR1, a dose well tolerated in human subjects for prevention of tissue injury, completely inhibited the in vivo clearance of the transfused RBCs and surface C3 deposition in the first hour after transfusion, correlating with the half-life of sCR1 in the circulation. Treatment with sCR1 increased the survival of transfused human group A RBCs in the circulation of mice with pre-existing anti-A for 2 hours after transfusion by 50%, reduced intravascular hemolysis, and lowered the levels of complement deposition (C3 and C4), but not immunoglobulin G (IgG) or IgM, on the transfused cells by 100-fold. We further identified potential functional domains in CR1 that can act to limit complement-mediated RBC destruction in vitro and in vivo. Collectively, our data highlight a potential use of CR1-based inhibitors for prevention of complement-dependent immune hemolysis.