Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

Abstract

Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem-or immune cells for the recipient, haplo-HCT represents a unique platform for cell-and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality.

Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease

“…Clinical BMT is mostly performed between MHCcompatible individuals (with minor histocompatibility antigens mismatches) and increasingly with hemi-incompatible ones (haploidentical, half HLA haplotype mismatch). 21 In this manuscript, we used F1 hemi-incompatible animal models (mouse and rat) that are representative of the clinical situation and we included a strong xenogeneic model using human cells into NSG mice emphasizing the translational significance of our data. Donor-specific immune tolerance was present and human GVT responses were preserved.…”

How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation

“…Going back to clinical studies, the pioneer pilot trial with the PTCy strategy led by the Baltimore group reported a very low incidence of grade III-IV aGVHD (10%) in patients transplanted with HLAhaploidentical BM after non-myeloablative conditioning regimen (138). Similar encouraging results were further observed by numerous other groups, even using PBSC as the stem cell source and more intensive conditioning regimens (139,144). Beyond haplo-alloHCT, PTCy recently starts gaining popularity in other settings, including HLA-matched sibling/ unrelated donor and HLA-mismatched unrelated donor alloHCT (145).…”

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

“…For children with high-risk leukemia in urgent need of a transplant, both parents can represent readily available haploidentical donors. However, to circumvent the risk of graft rejection and GvHD related to the high degree of HLA mismatch intrinsic to the haploidentical setting, different strategies have been exploited, including the use of post-transplant immune suppression or ex vivo graft manipulation to obtain an extensive T-cell depletion [13,[43][44][45]. The haplo-HSCT platform offered to the cohort of pediatric patients analyzed in this study took advantage of an innovative strategy based on the selective depletion of αβT lymphocytes (major responsible of GvHD) and CD19 + B cells (responsible of post-transplant EBV-related lymphoproliferative disorders) [46].…”