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NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells.

ABSTRACT: T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56lowCD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given ?/?T-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56lowCD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-? Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56lowCD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56lowCD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients.

SUBMITTER: Stabile H

PROVIDER: S-EPMC6912839 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells.

Stabile Helena H Nisti Paolo P Fionda Cinzia C Pagliara Daria D Gaspari Stefania S Locatelli Franco F Santoni Angela A Gismondi Angela A

Journal of clinical medicine 20191107 11

T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reco ...[more]

PMID: 31703320

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Project description:IntroductionHuman pegivirus-1 (HPgV-1) is a so-called commensal virus for which no known associated organ disease has been found to date. Yet, it affects immune-reconstitution as previously studied in the HIV population, in whom active co-infection with HPgV-1 can modulate T and NK cell activation and differentiation leading to a protective effect against the evolution of the disease. Little is known on the effect of HPgV-1 on immune-reconstitution in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, a patient population in which we and others have previously reported high prevalence of HPgV-1 replication. The aim of this study was to compare the immune reconstitution after allo-HSCT among HPgV-1-viremic and HPgV-1-non-viremic patients.MethodsWithin a cohort study of 40 allo-HSCT patients, 20 allo-HSCT recipients positive in plasma sample for HPgV-1 by rRT-PCR during the first year (1, 3, 6, 12 months) after transplantation were matched with 20 allo-HSCT recipients negative for HPgV-1. T and NK cell reconstitution was monitored by flow cytometry in peripheral blood samples from allo-HSCT recipients at the same time points.ResultsWe observed no significant difference in the absolute number and subsets proportions of CD4 and CD8 T cells between patient groups at any analysed timepoint. We observed a significantly higher absolute number of NK cells at 3 months among HPgV-1-viremic patients. Immunophenotypic analysis showed a significantly higher proportion of CD56bright NK cells mirrored by a reduced percentage of CD56dim NK cells in HPgV-1-positive patients during the first 6 months after allo-HSCT. At 6 months post-allo-HSCT, NK cell phenotype significantly differed depending on HPgV-1, HPgV-1-viremic patients displaying NK cells with lower CD16 and CD57 expression compared with HPgV-1-negative patients. In accordance with their less differentiated phenotype, we detected a significantly reduced expression of granzyme B in NK cells in HPgV-1-viremic patients at 6 months.DiscussionOur study shows that HPgV-1-viremic allo-HSCT recipients displayed an impaired NK cell, but not T cell, immune-reconstitution compared with HPgV-1-non-viremic patients, revealing for the first time a potential association between replication of the non-pathogenic HPgV-1 virus and immunomodulation after allo-HSCT.

Project description:IntroductionWe previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.MethodsCD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored.ResultsHLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline.DiscussionThese results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.

Dataset Information

NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells.

Publications

NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells.

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