scholarly journals Full Immunologic Reconstitution Following Nonconditioned Bone Marrow Transplantation for Canine X-Linked Severe Combined Immunodeficiency

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 3214-3221 ◽  
Author(s):  
Peter J. Felsburg ◽  
Richard L. Somberg ◽  
Brian J. Hartnett ◽  
Steven F. Suter ◽  
Paula S. Henthorn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
B Cells ◽  
Marrow Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Long Term Results ◽  
Pcr Analysis ◽  
Combined Immunodeficiency

Abstract Bone marrow transplantation in human X-linked severe combined immunodeficiency (XSCID) without pretransplant conditioning results in engraftment of donor T cells and reconstitution of T-cell function but engraftment of few, if any, donor B cells and poor reconstitution of humoral immune function. Since bone marrow transplantation remains the most effective treatment of XSCID patients, better strategies are necessary to achieve optimum long-term results. Canine XSCID, like human XSCID, is due to mutations in the common γ chain (γc) gene and has clinical and immunologic features identical to those of human XSCID, making it a true homolog of the human disease. We have successfully performed bone marrow transplantation in three XSCID dogs without pretransplant conditioning, using untreated bone marrow cells from mixed lymphocyte culture–nonreactive normal littermates. Unlike the experience in human XSCID patients, all three dogs engrafted both donor B and T cells and attained full reconstitution of immunologic function. Normal percentages of T cells and T-cell mitogenic responses were attained by 3 months posttransplant. CD3+ T cells after transplantation expressed the CD45RA isoform indicating that the cells were recent thymic emigrants derived from immature progenitors. Serum IgG levels were within normal range by 5 months posttransplant. Immunization with the T-dependent antigen, bacteriophage φX174, demonstrated normal antibody titers, immunologic memory, and class-switching. Polymerase chain reaction (PCR) analysis of the γc locus showed that 100% of circulating T cells and 30% to 50% of circulating B cells were donor-derived. None of the dogs developed clinically evident graft-versus-host disease (GVHD). Thus, canine XSCID provides a model to determine the optimal conditions for bone marrow transplantation in human patients, and to develop and test strategies for somatic gene therapy.

Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 880-885 ◽  
Author(s):  
Claudio Pignata ◽  
Lucia Gaetaniello ◽  
Anna Maria Masci ◽  
Jorge Frank ◽  
Angela Christiano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Cd8 Cells ◽  
Tcr Repertoire ◽  
Immunologic Reconstitution

Abstract Human Nude/SCID (severe combined immunodeficiency) is the first severe combined immunodeficiency caused by mutation of the winged–helix–nude (WHN) gene, which is expressed in the thymus but not in the hematopoietic lineage. The disease is characterized by a T-cell defect, congenital alopecia, and nail dystrophy. A Nude/SCID patient who underwent bone marrow transplantation from the human leukocyte antigen–identical heterozygote brother was studied to investigate, in this unique model, the role of the thymus in immunologic reconstitution. Despite an increase in CD3+, CD4+, and CD8+cells, CD4+ CD45 RA naive lymphocytes were not regenerated. Conversely, naive CD8+ cells were normal. After an initial recovery, lymphocyte proliferation to mitogens progressively declined compared with controls and genotypically identical donor cells grown in the WHN+/−environment. Analysis of the T-cell receptor (TCR) repertoire of CD4+ cells revealed that only 3 of 18 Vβ families had an altered CDR3 heterogeneity length profile. Conversely, CD8+lymphocytes showed an abnormal distribution in most Vβ families. These data indicate that the thymus is differentially required in the reconstitution of CD4+ and CD8+ naive subsets and in the maintenance of their TCR repertoire complexity. Taken together, these findings suggest that bone marrow transplantation is ineffective in the long-term cure of this form of SCID.

Long-Term Chimerism and B-Cell Function After Bone Marrow Transplantation in Patients With Severe Combined Immunodeficiency With B Cells: A Single-Center Study of 22 Patients

Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2923-2930 ◽  
Author(s):  
Elie Haddad ◽  
Françoise Le Deist ◽  
Pierre Aucouturier ◽  
Marina Cavazzana-Calvo ◽  
Stephane Blanche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
B Cell Function ◽  
Host Origin

We retrospectively analyzed the B-cell function and leukocyte chimerism of 22 patients with severe combined immunodeficiency with B cells (B+ SCID) who survived more than 2 years after bone marrow transplantation (BMT) to determine the possible consequences of BMT procedures, leukocyte chimerism, and SCID molecular deficit on B-cell function outcome. Circulating T cells were of donor origin in all patients. In recipients of HLA-identical BMT (n = 5), monocytes were of host origin in 5 and B cells were of host origin in 4 and of mixed origin in 1. In recipients of HLA haploidentical T-cell–depleted BMT (n = 17), B cells and monocytes were of host origin in 14 and of donor origin in 3. Engraftment of B cells was found to be associated with normal B-cell function. In contrast, 10 of 18 patients with host B cells still require Ig substitution. Conditioning regimen (ie, 8 mg/kg busulfan and 200 mg/kg cyclophosphamide) was shown neither to promote B-cell and monocyte engraftment nor to affect B-cell function. Eight patients with B cells of host origin had normal B-cell function. Evidence for functional host B cells was further provided in 3 informative cases by Ig allotype determination and by the detection, in 5 studied cases, of host CD27+ memory B cells as in age-matched controls. These results strongly suggest that, in some transplanted patients, host B cells can cooperate with donor T cells to fully mature in Ig-producing cells.

T-cell-depleted maternal bone marrow transplantation for siblings with X-linked severe combined immunodeficiency

1993 ◽  
Vol 122 (2) ◽  
pp. 289-291 ◽  
Author(s):  
Bruce P. Himelstein ◽  
Jennifer Puck ◽  
Charles August ◽  
Giuliana Pierson ◽  
Nancy Bunin
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency

Full hematopoietic engraftment after allogeneic bone marrow transplantation without cytoreduction in a child with severe combined immunodeficiency

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 809-811 ◽  
Author(s):  
Ronald J. Rubocki ◽  
Jennifer R. Parsa ◽  
Michael S. Hershfield ◽  
Warren G. Sanger ◽  
Samuel J. Pirruccello ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Severe Combined Immunodeficiency ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Combined Immunodeficiency ◽  
Cell Functions

Abstract Bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) with human leukocyte antigen (HLA)-identical sibling donors but no pretransplantation cytoreduction results in T-lymphocyte engraftment and correction of immune dysfunction but not in full hematopoietic engraftment. A case of a 17-month-old girl with adenosine deaminase (ADA) deficiency SCID in whom full hematopoietic engraftment developed after BMT from her HLA-identical sister is reported. No myeloablative or immunosuppressive therapy or graft-versus-host disease (GVHD) prophylaxis was given. Mild acute and chronic GVHD developed, her B- and T-cell functions became reconstituted, and she is well almost 11 years after BMT. After BMT, repeated studies demonstrated: (1) Loss of a recipient-specific chromosomal marker in peripheral blood leukocytes (PBLs) and bone marrow, (2) conversion of recipient red blood cell antigens to donor type, (3) conversion of recipient T-cell, B-cell, and granulocyte lineages to donor origin by DNA analysis, and (4) increased ADA activity and metabolic correction in red blood cells and PBLs.

scholarly journals Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1944-1953 ◽  
Author(s):  
R Bacchetta ◽  
R Parkman ◽  
M McMahon ◽  
K Weinberg ◽  
M Bigler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Severe Combined Immunodeficiency ◽  
Host Cells ◽  
Combined Immunodeficiency ◽  
Clonal Deletion ◽  
T Cell Clones ◽  
Cell Clones

We have investigated the mechanism of tolerance in a patient with severe combined immunodeficiency (SCID) transplanted with HLA-haploidentical, T cell-depleted bone marrow cells obtained from the mother. At 4 years after transplantation, T cells, natural killer (NK) cells, and a small percentage (2%) of B cells were found to be of donor origin, whereas monocytes and the majority of B cells remained of host origin. In primary mixed lymphocyte cultures (MLC), the engrafted T cells of the donor did not proliferate in response to the host cells, whereas untransplanted donor T cells showed good proliferative responses. However, CD4+ and CD8+ T-cell clones of donor origin with specificity for class II and class I HLA determinants of the host were isolated. CD8+, host-reactive T-cell clones displayed normal cytotoxic activity after stimulation with the host cells, but proliferative responses of CD4+, host-reactive T-cell clones were considerably reduced. In addition, both CD8+ and CD4+, host-reactive T-cell clones produced very low to undetectable levels of interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3 zeta subunit of the T-cell receptor (TcR) was normal, and after stimulation via CD3, Raf-1 and p42 mitogen activated protein (MAP) kinase were phosphorylated, indicating that this part of the signaling pathway after triggering of the TcR/CD3 complex is present. These results, together with our previous observation that dysfunctional, host-reactive T-cell clones can be isolated in SCID patients transplanted with fetal liver stem cells, demonstrate that lack of clonal deletion of host-reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.

Tolerance of engrafted donor T cells following bone marrow transplantation for severe combined immunodeficiency

1988 ◽  
Vol 48 (3) ◽  
pp. 261-276 ◽  
Author(s):  
Carolyn A. Keever ◽  
Neal Flomenberg ◽  
Joel Brochstein ◽  
Mary Sullivan ◽  
Nancy H. Collins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Donor T Cells
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