The common cause of GF is host immunologic reaction against donor cells, so called graft rejection

The common cause of GF is host immunologic reaction against donor cells, so called graft rejection. to less than 5%. 1. Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) using one human leukocyte antigen (HLA) haplotype matched first-degree relative donor (haploidentical donor) represents an alternative treatment for patients with hematologic malignancies who lack HLA-matched related or unrelated donor. Historically, the main limitations of this treatment modality were high rate of graft failure (GF) and graft-versus-host disease (GVHD), which occur due to intense alloreactive reactions related to the major HLA mismatch between the recipient and the donor. Although several approaches have been developed which aimed MK-2 Inhibitor III to partially deplete T cells in the graft and decrease graft-versus-host alloreactivity, GF remains a major obstacle [1C3]. While increased rate of engraftment has occurred with the use of megadoses of hematopoietic MK-2 Inhibitor III stem cells (over 10 million CD34+ cells/kg with a very low T cell content) (1 104 CD3+ cells/kg) [4, 5], approximately 10C20% of patients still developed GF [6C8]. The increased risk of GF following haploidentical stem cell transplant (haploSCT) is due, in part, to an enhanced susceptibility of the MK-2 Inhibitor III graft to regimen-resistant host natural killer (NK) cell- and T lymphocyte-mediated rejection against mismatched donor cells [9, 10]. In addition to T cell- and NK-cell-mediated graft rejection (cellular rejection), antibody-mediated rejection (humoral rejection) occurring either by antibody-dependent cell-mediated cytotoxicity or match mediated cytotoxicity has been explained [11, 12]. Preformed donor-specific anti-HLA antibodies (DSAs) present at the time of transplant have been shown to be correlated with graft rejection and decrease survival in solid organ transplantation [13C16]. Therefore, lymphocyte crossmatch assessments have been developed for prediction of graft rejection [17, 18] and became required in solid organ transplant according to the American Society for Histocompatibility and Immunogenetics (ASHI). In AHSCT setting, there has been reported that a positive crossmatch for anti-donor lymphocytotoxic antibody associated strongly with GF, mainly in mismatched or haploSCT patients [19, 20]. Although Rabbit Polyclonal to SHANK2 a lymphocyte crossmatch is an effective tool to evaluate alloimmunization and potential donor-recipient incompatibility, the procedure is labor rigorous and may detect non-HLA antibodies, which may not be associated with transplant end result since there is no data to confirm the importance of these antibodies to date. Over the recent years, several methods have been developed to more precisely detect and characterize DSAs MK-2 Inhibitor III in AHSCT recipients [21, 22], and also the obvious association between the presence of these antibodies and GF has been confirmed especially in mismatched and haploSCT patients [14, 23, 24]. Still, the mechanisms by which DSA may cause GF in AHSCT remain an area of active research. Here we review the potential mechanisms and clinical importance of DSAs on GF in haploSCT, as well as treatment modalities utilized for DSA desensitization before transplant to abrogate the risk of GF and improve transplant outcomes. 2. Mechanisms of Graft Rejection in Haploidentical Stem Cell Transplantation Engraftment failure rate has been approximately 4% in AHSCT using matched unrelated donors and about 20% in umbilical cord blood (UCB) or T cell-depleted haploSCT [25, 26]. The common cause of GF is host immunologic reaction against donor cells, so called graft rejection. Graft rejection following haploSCT is generally attributed to cytolytic host-versus-graft reaction mediated by host T and/or NK-cells that survived the conditioning regimen. However, antibody-mediated graft rejection (normally known as humoral rejection) has been increasingly recognized in the past decade. 2.1. Cellular-Mediated Graft Rejection The resistance to engraftment of AHSCT was thought to be mediated primarily by recipient T lymphocytes which depends on the genetic disparity between the donor and recipient and the status of host antidonor reactivity [27]. This makes mismatched and haploSCT recipients likely more susceptible to develop graft rejection compared with matched AHSCT due to stronger alloreactive reactions in this setting. It has been found in animal model of stem cell transplantation that antidonor cytotoxic T cells sensitized to major and minor histocompatibility (MHC) antigens confer resistance against allogeneic MK-2 Inhibitor III bone marrow stem cells [28]. This obtaining also has been confirmed in clinical studies of AHSCT in patients with severe aplastic anemia, in which the presence of radioresistant antidonor cytotoxic T cell populations sensitized to donor MHC antigens through repeated blood transfusions is.