The Evolution of T Cell Depleted Haploidentical Transplantation

Aversa, Franco; Pierini, Antonio; Ruggeri, Loredana; Martelli, Massimo F.; Velardi, Andrea

doi:10.3389/fimmu.2019.02769

Cited by 32 publications

(25 citation statements)

References 87 publications

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“…Destruction of bone marrow by irradiation or chemotherapy could be done prior to experimental TBI; however, mice are incredibly vulnerable to opportunistic infection, inflammatory response due to tissue damage, respiratory distress, dehydration, bleeding, and death in the weeks following myeloablation 97 . A more precise and informative strategy could include transplantation of T cell depleted hematopoietic progenitors or post-transplant depletion of immune cell subsets via antibody-based blocking, immunosuppressive agents, pretreatment with liposomal clodronate, and/or genetic targeting of the human immune cells 98,99 .…”

Section: Discussionmentioning

confidence: 99%

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Díaz

Horton

Kumar

et al. 2020

Sci Rep

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The immune system plays critical roles in promoting tissue repair during recovery from neurotrauma but is also responsible for unchecked inflammation that causes neuronal cell death, systemic stress, and lethal immunodepression. Understanding the immune response to neurotrauma is an urgent priority, yet current models of traumatic brain injury (TBI) inadequately recapitulate the human immune response. Here, we report the first description of a humanized model of TBI and show that TBI places significant stress on the bone marrow. Hematopoietic cells of the marrow are regionally decimated, with evidence pointing to exacerbation of underlying graft-versus-host disease (GVHD) linked to presence of human T cells in the marrow. Despite complexities of the humanized mouse, marrow aplasia caused by TBI could be alleviated by cell therapy with human bone marrow mesenchymal stromal cells (MSCs). We conclude that MSCs could be used to ameliorate syndromes triggered by hypercytokinemia in settings of secondary inflammatory stimulus that upset marrow homeostasis such as TBI. More broadly, this study highlights the importance of understanding how underlying immune disorders including immunodepression, autoimmunity, and GVHD might be intensified by injury. Traumatic brain injury (TBI) is a major contributor to long-term disability and mortality in children and adults, and, despite intensive efforts, there are no effective treatments for TBI 1,2. Sequelae of TBI and soft tissue injuries resulting from polytrauma include changes in cerebral metabolism, excitotoxicity, induction of emergency hematopoiesis, infiltration of fluid and inflammatory cells into the brain, systemic cytokine storm and localized cytokine release, and activation of microglia, the resident macrophage of the central nervous system 3-8. The immune system plays critical roles in promoting tissue repair and clearance of dying neurons during recovery from neurotrauma but is also responsible for the deleterious inflammation that kills healthy neurons. Systemic immunodepression and vulnerability to infection often follow the acute phase of TBI wherein hypercytokinemia and inflammation resolve, placing patients at increased risk of pneumonia and sepsis 9. Thus, understanding the contribution of the immune system to recovery is critical to development of efficacious therapies for neurotrauma 10,11 .

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Section: Discussionmentioning

confidence: 99%

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Díaz

Horton

Kumar

et al. 2020

Sci Rep

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“…To overcome this obstacle, over the last few decades, many strategies have been developed to improve the feasibility and safety of haplo-HCT (1,2). In particular, two main haplo-HCT "philosophies" were progressively refined over the years: the ex vivo manipulation of the graft to deplete the most alloreactive cell subsets (3), eventually reinfusing them in a subsequent moment in combination with regulatory T cells (4,5) or upon incorporation of safety switches (6)(7)(8), vs. the infusion of unmanipulated grafts, followed by administration of drugs capable of eliminating alloreactive cells in vivo (9,10). Noticeably, some of these platforms have demonstrated remarkable success, leading to an exponential increase in the number of haplo-HCT performed worldwide (11,12).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Meazza

Falco

Loiacono

et al. 2020

Cancers

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NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.

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The Evolution of T Cell Depleted Haploidentical Transplantation

Cited by 32 publications

References 87 publications

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

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

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