Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)–identical and HLA-nonidentical stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4344-4349 ◽  
Author(s):  
Susanna M. Müller ◽  
Thomas Kohn ◽  
Ansgar S. Schulz ◽  
Klaus-Michael Debatin ◽  
Wilhelm Friedrich
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Human Leukocyte Antigen ◽  
Progenitor Cells ◽  
Severe Combined Immunodeficiency ◽  
Human Leukocyte ◽  
Combined Immunodeficiency ◽  
Leukocyte Antigen

Abstract Donor T cells after stem cell transplantation reconstitute by 2 different pathways: by expansion from grafted, mature T cells and by intrathymic maturation from progenitor cells. This study characterized thymic-dependent reconstitution of CD4+ T cells following different transplant modalities in patients with severe combined immunodeficiency (SCID). Three groups of patients were studied: one group after transplantation from human leukocyte antigen (HLA)–identical siblings with unmanipulated grafts without conditioning, a second group after transplantation from HLA-nonidentical parents with T-cell–depleted grafts without preconditioning, and a third group with prior conditioning. Reconstitution of the T-cell compartment was monitored by determining the expression of CD45 isoforms by developing CD4+ cells in the peripheral blood and in discriminating expanded (CD45RO+) and newly generated (CD45RA+) T cells. Concomitantly, changes in the size of the thymus were evaluated sequentially by ultrasonography. Reconstitution of CD4+CD45RA+ cells was delayed in all patients for several months, including patients after HLA-identical transplantation, and was always paralleled by normalization of the size of the thymus. No engraftment of donor progenitor cells was observed, as studied in one patient transplanted without conditioning. CD4+CD45RO+ cells were detected early after transplantation only in patients given unmanipulated grafts. The study showed that thymic-dependent T-cell maturation in these patients with SCID runs an autonomous course, independent of graft manipulation, of major HLA disparities, and of whether conditioning is used or not. In addition, thymic maturation may not require engraftment of donor-derived CD34+ cells in the marrow.

Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)–identical and HLA-nonidentical stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4344-4349 ◽  
Author(s):  
Susanna M. Müller ◽  
Thomas Kohn ◽  
Ansgar S. Schulz ◽  
Klaus-Michael Debatin ◽  
Wilhelm Friedrich
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Human Leukocyte Antigen ◽  
Progenitor Cells ◽  
Severe Combined Immunodeficiency ◽  
Human Leukocyte ◽  
Combined Immunodeficiency ◽  
Leukocyte Antigen

Donor T cells after stem cell transplantation reconstitute by 2 different pathways: by expansion from grafted, mature T cells and by intrathymic maturation from progenitor cells. This study characterized thymic-dependent reconstitution of CD4+ T cells following different transplant modalities in patients with severe combined immunodeficiency (SCID). Three groups of patients were studied: one group after transplantation from human leukocyte antigen (HLA)–identical siblings with unmanipulated grafts without conditioning, a second group after transplantation from HLA-nonidentical parents with T-cell–depleted grafts without preconditioning, and a third group with prior conditioning. Reconstitution of the T-cell compartment was monitored by determining the expression of CD45 isoforms by developing CD4+ cells in the peripheral blood and in discriminating expanded (CD45RO+) and newly generated (CD45RA+) T cells. Concomitantly, changes in the size of the thymus were evaluated sequentially by ultrasonography. Reconstitution of CD4+CD45RA+ cells was delayed in all patients for several months, including patients after HLA-identical transplantation, and was always paralleled by normalization of the size of the thymus. No engraftment of donor progenitor cells was observed, as studied in one patient transplanted without conditioning. CD4+CD45RO+ cells were detected early after transplantation only in patients given unmanipulated grafts. The study showed that thymic-dependent T-cell maturation in these patients with SCID runs an autonomous course, independent of graft manipulation, of major HLA disparities, and of whether conditioning is used or not. In addition, thymic maturation may not require engraftment of donor-derived CD34+ cells in the marrow.

Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4360-4367 ◽  
Author(s):  
Tobias Feuchtinger ◽  
Kathrin Opherk ◽  
Wolfgang A. Bethge ◽  
Max S. Topp ◽  
Friedhelm R. Schuster ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Human Leukocyte Antigen ◽  
Adoptive Transfer ◽  
Human Leukocyte ◽  
Cmv Infection ◽  
Leukocyte Antigen ◽  
Cmv Disease

Abstract Cytomegalovirus (CMV) disease and infection refractory to antiviral treatment after allogeneic stem cell transplantation (allo-SCT) is associated with a high mortality. Adoptive transfer of CMV-specific T cells could reconstitute viral im-munity after SCT and could protect from CMV-related complications. However, logistics of producing virus-specific T-cell grafts limited the clinical application. We treated 18 patients after allo-SCT from human leukocyte antigen–mismatched/haploidentical or human leukocyte antigen–matched unrelated donors with polyclonal CMV-specific T cells generated by ex vivo stimulation with pp65, followed by isolation of interferon-γ–producing cells. Patients with CMV disease or viremia refractory to antiviral chemotherapy or both were eligible for adoptive T-cell transfer and received a mean of 21 × 103/kg pp65-specific T cells. In 83% of cases CMV infection was cleared or viral burden was significantly reduced, even in cases of CMV encephalitis (n = 2). Viral control was associated with in vivo expansion of CMV-specific T lymphocytes in 12 of 16 evaluable cases, resulting in reconstitution of antiviral T-cell responses, without graft-versus-host disease induction or acute side effects. Our findings indicate that the infusion of low numbers of CMV-specific T cells is safe, feasible, and effective as a treatment on demand for refractory CMV infection and CMV disease after allo-SCT.

scholarly journals Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID

2021 ◽  
Vol 12 ◽  
Author(s):  
Jolanda Steininger ◽  
Alexander Leiss-Piller ◽  
Christoph B. Geier ◽  
Raphael Rossmanith ◽  
Reem Elfeky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Cell Recovery ◽  
Hematopoietic Stem

Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3’ splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαβ/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT.

scholarly journals Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2227-2236 ◽  
Author(s):  
NA Kernan ◽  
C Bordignon ◽  
G Heller ◽  
I Cunningham ◽  
H Castro-Malaspina ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Graft Failure ◽  
Human Leukocyte ◽  
Marrow Transplant ◽  
High Dose ◽  
Leukocyte Antigen ◽  
Major Factors

Abstract Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1,375 to 1,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/d x 2). No patient received immunosuppression prosttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor-derived grafts a low dose per kilogram of nucleated cells, progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1,500 cGy, high dose corticosteroids posttransplant, and additional peripheral blood donor T cells did not decrease the incidence of graft failure. In addition, type of leukemia, time from diagnosis to transplant, an intact spleen, or the presence of antidonor leukocyte antibodies did not correlate with graft failure. To ensure engraftment of secondary transplants, further immunosuppression was necessary but was poorly tolerated. However, engraftment and survival could be achieved with an immunosuppressive regimen in which antithymocyte globulin and high dose methylprednisolone were administered both before and after infusions of secondary partially T- cell-depleted marrow grafts.

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