Transplant Outcomes for Primary Immunodeficiency Disease

doi:10.1053/j.seminhematol.2009.10.001

Seminars in Hematology

Volume 47, Issue 1, January 2010, Pages 79-85

https://doi.org/10.1053/j.seminhematol.2009.10.001 Get rights and content

Primary immune deficiencies (PIDs) are rare diseases, and most are lethal without appropriate intervention. Hematopoietic cell transplantation (HCT) can cure the majority of patients, but most lack a suitable matched related donor. Alternative donor stem cells (mismatched related donor bone marrow, unrelated donor bone marrow, and unrelated donor umbilical cord blood [UCB]) are therefore frequently required. Published data comparing outcomes after alternative donor transplant for PID are scarce. The outcomes and potential advantage and disadvantages of each alternative stem cell source are discussed in this chapter. Although there are insufficient prospective data to make meaningful comparisons between the alternative stem cell sources, the results presented here demonstrate clearly that the use of UCB transplantation for PID is a viable option and may be advantageous in many situations.

Section snippets

Alternative Donor Transplant for Primary Immunodeficiencies

HCT can cure the majority of patients with PID. Although stem cells from a matched related donor (MRD) are preferred, that option exists for only a minority of patients, leaving alternative donor stem cell sources as the necessity for most. For reasons that have been discussed elsewhere in this issue, in the context of transplant for PID, potential advantages of UCB include rapid access to the donor unit, allowing for a speedy transplant in patients at very high risk for life-threatening

Wiskott-Aldrich Syndrome

Prior to 1968, when the first successful HCT for WAS was performed,⁵ supportive therapy, including transfusions and splenectomy, was the only option for these patients. The first transplants for WAS were performed using HLA MRDs. Long-term follow-up of these patients demonstrated that, when transplanted early with both myeloablative and immunosuppressive therapy, the majority of patients were alive with normal platelet counts and immune function.⁶ However, early reports cautioned against using

Summary

Although there are insufficient data to perform meaningful comparisons among the alternative stem cell sources, the results described here demonstrate clearly that the use of UCB transplantation for PID states is a reasonable option and may even be advantageous in some situations (Table 2). UCB provides a rapidly available donor stem cell source for children with SCID and likely this source can be utilized in the setting of reduced-intensity conditioning regimens to achieve full donor

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Cited by (11)

In vivo reversion of an inherited mutation in a Chinese patient with Wiskott-Aldrich syndrome
2015, Human Immunology
Citation Excerpt :
Revertant mutations may originate at various stages of T-cell development and may arise in T-cells of distinct antigenic specificity; therefore, the frequency distribution of revertant genotypes in a given patient will necessarily reflect this history, as well as the strength and timing of various immune challenges. The autoimmune manifestations may also be caused by the presence of residual WASP-negative autoreactive lymphocytes, as suggested by the striking observation that most patients with WAS with mixed chimerism after hematopoietic stem cell transplantation develop autoimmunity [23–25]. No WASP-expression and reversion genotypes were detected in CD34+ cells from bone marrow.
A spontaneous reversion that restores Wiskott–Aldrich syndrome protein (WASP) expression was reported recently. However, the genetic mechanism underlying the reversion event was unclear. In the present study, a WAS patient with a nonsense mutation (155 C > T, R41X) was followed during a three-year period. No expression of WASP was detected in peripheral blood mononucleated cells (PBMCs) in 2009 and a small population of intracellular WASP positive lymphocytes was detected during the following three years. The increasing trend of the revertant genotype was significant. WASP-expressing cells were present mainly CD56+ NK cells and CD8+ T cells. Sorted WASP+ cells were analyzed, indicating that the population of CD3+ T cells increased from 36.81% to 99.8%. Although the revertant cells in vivo may have a growth advantage, the patient presented a persistent autoimmune disease, thrombocytopenia, and died from extensive pulmonary fibrosis. The results suggest that the clinical consequences of T-cell mosaicism in WAS remain difficult to predict and is not sufficient to fully normalize immune functions in patients with WAS.
T-cell receptor excision circles and repertoire diversity in children with profound T-cell immunodeficiency
2013, Journal of Microbiology, Immunology and Infection
Citation Excerpt :
The clinical manifestations of PIDs with identified genetic defects are more predictable, because a relationship between genotype and phenotype exists despite rare exceptions.4–6 In cases still without identified genetic defects, immune functional analysis has become more important and practical for aggressive intervention, like hematopoietic stem cell transplantation (HSCT), which is mandatory for rescuing PIDs with severe T and phagocytic disorders.7–11 In patients with profound T-cell immunodeficiency of <30% mitogen [e.g., phytohemagglutinin (PHA)] proliferation function in healthy individuals,12 often presenting as severe combined T and B immunodeficiency (SCID)], >95% of SCID patients have successful HSCT and excellent prognosis if diagnosed and transplanted before the age of 3 months.9,13
Approximately 40% of patients with profound T-cell immunodeficiency have no identified molecular basis. Early assessment of T-cell impairment is vital for medical intervention, if hematopoietic stem cell transplantation is needed. The dynamics of T-cell receptor excision circles (TRECs) revealing recent thymic output of naïve T cell and T-cell receptor (TCR) repertoire diversity reflecting broader responses to multiple antigens, are both important in resisting infections.
The TRECs value and TCR repertoire diversity were evaluated from peripheral blood mononuclear cells in patients with primary severe T cell immunodeficiency, to elucidate the T-cell response.
In seven children with <30% of normal phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, including two IL2RG (Try74Gly and Arg226Lys, X-linked) and one RAG2 mutations [(Ser205Tyr) and (del 1366T, frameshift, 484stop); autosomal recessive], lower TRECs value and oligo- and restricted TCR diversity patterns, were associated with increased susceptibility to opportunistic infections, but not inversely correlated to the severity and frequency of infections. Three patients had successful cord blood stem cell transplantation which reconstructed the T cell immunodeficiency, with normalized TRECs value and TCR repertoire diversity at 6 months post-transplant, without clinical events.
Low TRECs value and restricted TCR repertoire diversity can help in the early diagnosis of T cell immunodeficiency before irreversible sequelae and in the monitoring of post-transplantation T-cell immune reconstruction.
Correction of murine rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene
2012, Molecular Therapy
Citation Excerpt :
Recombination activating gene 2 (RAG2) deficiency is an autosomal recessive disorder causing a complete lack of mature T and B lymphocytes leading to severe combined immunodeficiency (SCID). HLA-identical bone marrow (BM) transplantation is the treatment of choice, but due to limited availability of HLA-matched donors alternative donor stem cell sources are a necessity for most SCID patients, however limited in efficacy and with variable outcomes.1 Recently, gammaretroviral gene therapy has demonstrated long-term clinical efficacy for X-linked SCID (SCID-X1)2,3,4 and adenosine deaminase-SCID5 by complementation of a correct copy of the defected gene.
Recombination activating gene 2 (RAG2) deficiency results in severe combined immunodeficiency (SCID) with complete lack of T and B lymphocytes. Initial gammaretroviral gene therapy trials for other types of SCID proved effective, but also revealed the necessity of safe vector design. We report the development of lentiviral vectors with the spleen focus forming virus (SF) promoter driving codon-optimized human RAG2 (RAG2co), which improved phenotype amelioration compared to native RAG2 in Rag2^−/− mice. With the RAG2co therapeutic transgene, T-cell receptor (TCR) and immunoglobulin repertoire, T-cell mitogen responses, plasma immunoglobulin levels and T-cell dependent and independent specific antibody responses were restored. However, the thymus double positive T-cell population remained subnormal, possibly due to the SF virus derived element being sensitive to methylation/silencing in the thymus, which was prevented by replacing the SF promoter by the previously reported silencing resistant element (ubiquitous chromatin opening element (UCOE)), and also improved B-cell reconstitution to eventually near normal levels. Weak cellular promoters were effective in T-cell reconstitution, but deficient in B-cell reconstitution. We conclude that immune functions are corrected in Rag2^−/− mice by genetic modification of stem cells using the UCOE driven codon-optimized RAG2, providing a valid optional vector for clinical implementation.
Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency
2011, Blood
Citation Excerpt :
Mutations in GATA2 were also reported as a cause of familial MDS/AML.5 Many primary immunodeficiency diseases are caused by intrinsic genetic defects of hematopoietic lineage-derived cells for which allogeneic HSCT represents an effective therapeutic approach.6 Because of the lethal nature of GATA2 deficiency,1 we sought to reconstitute the deficient hematopoietic compartments using allogeneic HSCT.
We performed nonmyeloablative HSCT in 6 patients with a newly described genetic immunodeficiency syndrome caused by mutations in GATA2—a disease characterized by nontuberculous mycobacterial infection, monocytopenia, B- and NK-cell deficiency, and the propensity to transform to myelodysplastic syndrome/acute myelogenous leukemia. Two patients received peripheral blood stem cells (PBSCs) from matched-related donors, 2 received PBSCs from matched-unrelated donors, and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched-related and -unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI); UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB, GVHD in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplantation. Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype. Registered at www.clinicaltrials.gov as NCT00923364.
Cord blood banking and transplantation in 2010
2010, Transfusion and Apheresis Science
Novel Human Umbilical Di-Chimeric (HUDC) cell therapy for transplantation without life-long immunosuppression
2023, Stem Cell Investigation

View all citing articles on Scopus

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Transplant Outcomes for Primary Immunodeficiency Disease

Section snippets

Alternative Donor Transplant for Primary Immunodeficiencies

Wiskott-Aldrich Syndrome

Summary

Lancet

Lancet

Blood

Blood

Blood

J Pediatr

Blood

J Pediatr

Blood

Lancet

Blood

Blood

Blood

Blood

J Allergy Clin Immunol

Reprod Biomed Online

Hemopoietic stem cell transplantation using mouse bone marrow and spleen cells fractionated by lectins

Proc Natl Acad Sci U S A

Bone marrow transplantation in rats across strong histocompatibility barriers by selective elimination of lymphoid cells in donor marrow

Transplant Proc

Cord blood stem cell transplantation in primary immune deficiencies

Curr Opin Allergy Clin Immunol

Bone marrow transplantation for the Wiskott-Aldrich syndromeLong-term follow-up

Transplantation

Successful unmanipulated haploidentical bone marrow transplantation from an HLA 2-locus-mismatched mother for Wiskott-Aldrich syndrome after unrelated cord blood stem cell transplantation

J Pediatr Hematol Oncol