Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients

Graft failure is a major concern after cord blood transplantation (CBT) or HLA-haploidentical transplantation (haplo-SCT). As patients who undergo CBT or haplo-SCT almost always lack both matched-related and -unrelated donors, salvage transplantation would also be limited to either CBT or haplo-SCT. In this study, we assessed eight patients who received haplo-SCT as salvage therapy for graft failure. Five and three patients had received haplo-SCT and CBT, respectively, which resulted in graft failure. The median interval from the failed transplantation to salvage transplantation in six patients with primary graft failure was 33.5 days. The reducedintensity conditioning regimen consisted of fludarabine, thiotepa, rabbit antithymocyte globulin and low-dose TBI. All eight patients achieved neutrophil engraftment, and seven patients achieved platelet recovery. The median times to neutrophil recovery and platelet recovery were 10 and 20 days, respectively. Three patients died from treatment-related causes: two from GVHD and one from rupture of carotid artery aneurysm. Five patients are alive, at a median follow-up of 946 days. The probability of overall survival at 5 years was 75%. These findings may serve as a rationale for giving precedence to haplo-SCT over CBT in salvage SCT after graft failure.

Section: Introductionmentioning

confidence: 99%

Salvage haploidentical transplantation for graft failure using reduced-intensity conditioning

Yoshihara

Ikegame

Taniguchi

et al. 2011

“…7,8 In patients receiving major HLA-Ag mismatched allo-SCT, a positive crossmatch has been significantly correlated to increased risk for graft failure and inferior survival as compared with patients transplanted against a negative crossmatch. 9,10 Taken together, on the basis of the above-mentioned publications, we have on a regular basis performed cytotoxic crossmatches in allo-SCT patients before transplantation since 2000.…”

Section: Discussionmentioning

confidence: 99%

“…6 However, recent data from mouse models indicate that the presence of preformed donor-reactive Abs is a dominant barrier for BM engraftment in allosensitized recipients. 7,8 In contrast to organ transplantation, data on the clinical outcome after allo-SCT across a positive crossmatch are scarce. Previous work by Anasetti et al 9 showed that patients with a positive crossmatch had a significantly increased risk of rejection compared with patients with a negative crossmatch.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic crossmatch analysis before allo-SCT is a poor diagnostic tool for prediction of rejection

Mattsson

Nordlander

Remberger

et al. 2009

The predictive value of cytotoxic crossmatch analysis before allo-SCT remains unclear. We retrospectively analyzed the clinical impact of cytotoxic T-and B-cell crossmatch testing before allo-SCT between January 2000 and June 2005. Cytotoxic crossmatches were performed in 157 patients receiving stem cells from matched unrelated donors or an HLA-A, -B or -DRB1 allele mismatched graft. Ninety patients are still alive. Eleven patients rejected their grafts. One of 11 patients with rejection was positive in a T-cell crossmatch before allo-SCT and 4 of 11 in B-cell crossmatches. T-cell crossmatches showed a sensitivity of 9% and a specificity of 97% compared with 36 and 86% for B-cell crossmatches. Positive T-and/or B-crossmatch before SCT had no predictive value for survival in this study as compared with patients with a negative crossmatch. In conclusion, the pretransplant cytotoxic T-and/or B-crossmatch is a poor predictor of rejection after allo-SCT.

“…This finding is consistent with early reports that the majority of hematopoietic progenitor cells co-express HLA-DR 45,46 and that CD4 + T cells recognizing mismatched HLA-DR Ag can be associated with graft failure. 47 Recently, some animal studies suggest that humoral immunity is the major barrier to engraftment, 48,49 although cellular immunity has been recognized as the primary mechanism of rejection. 7 In this study, we could not determine whether humoral or cellular immunity would be a dominant barrier to engraftment.…”

Section: Discussionmentioning

confidence: 99%

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection

Hanajiri

Murata

Sugimoto

et al. 2015

In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8 + T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.