Patient 4 (sibling to patient 3) was well until he presented with inflammatory colitis and Hodgkin lymphoma (inguinal and para-aortic region) at age 16 years. Because of his sibling's history, CTLA4 ...haploinsufficiency was confirmed by both genetic and protein level testing, the only patient in this cohort to have an identified mutation before HSCT. In summary, 4 of 8 patients experienced GvHD despite having well-matched donors and receiving alemtuzumab in 3 out of 4 cases.\n9 (5.4-16.8)IgA 0.27 (0.74-2.61)IgM 0.84 (0.40-1.95)Preimmunoglobulin therapyPre-RTX 23 y Interstitial lung disease ("nodular lymphoid hyperplasia") Transverse myelitis Recurrent white matter and brainstem lesions with oligoclonal bands and elevated IgG index Arthritis Father:ITPSister:Patient no. 7 Table I Patients' characteristics ABVD, Adriamcyin (Doxorubicin), bleomycin, vinblastine, dacarbazine; naive CD4, CD3+CD4+CD27+CD45RA+; naive CD8, CD3+CD4-CD27+CD45RA+; Euronet PHL-C1, Euronet pediatric Hodgkin lymphoma-C1; F, female; IDDM, insulin-dependent diabetes mellitus; ITP, idiopathic thrombocytopenic purpura; M, male; NK, natural killer; PN, parenteral nutrition; RTX, rituximab.
The use of HLA-haploidentical family donors requires T-cell depletion to avoid graft-versus-host disease (GVHD), which increases the risk of graft rejection, particularly for patients with forms of ...primary immunodeficiency other than severe combined immune deficiency.3 Various T-cell depletion strategies have been used to minimize GVHD and maximize sustained engraftment and early immune reconstitution, such as enrichment of CD34+ cells or depletion of CD3+ and CD19+ cells to prevent post-transplant lymphoproliferative disorder. The drawback of positive CD34+ selection is that a large number of effector cells, such as natural killer (NK), myeloid, and plasmacytoid dendritic cells--which aid engraftment and also decrease the risk of infection--are lost.
Background Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for ...preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. Objective To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. Methods A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK+ (n = 24) and NK− (n = 53) forms of SCID. Results Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK− SCID were more likely to survive than NK+ recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK+ SCID required additional transplantation procedures compared with only 8% of children with NK− SCID ( P < .005). Conclusions NK− SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.
The anti-CD52-treated product contains component blood cell precursors, cells in early differentiation, and stromal factors that aid HSC engraftment into the bone marrow niche.5 In a retrospective ...study, we suggested that better donor stem cell, myeloid, and B-lymphocyte engraftment is found in patients with SCID who received anti-CD52-depleted rather than CD34+-selected HSCs.6 In addition, by targeting T lymphocytes and B lymphocytes, CD3/CD19-depleted grafts retain CD34+ stem cells and engraftment-enhancing CD34- progenitors and natural killer, dendritic, and graft-facilitating cells.7 Previous reports of CD3/CD19-depleted peripheral blood stem cell (PBSC) transplants are from patients with malignant disease.5,8,9 Between 1999 and 2006, we transplanted 6 patients with SCID who had viral infections with CD34+ selected haploidentical grafts: 2 had cytomegalovirus (CMV), detailed in this report. Since 2006, 4 patients with SCID have been transplanted by using haploidentical stem cells depleted of CD3/CD19+ cells, 3 with viral infections described in this report.
Background Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency. BCG vaccine is contraindicated in patients with SCID. Because most countries encourage ...BCG vaccination at birth, a high percentage of patients with SCID are vaccinated before their immune defect is detected. Objectives We sought to describe the complications and risks associated with BCG vaccination in patients with SCID. Methods An extensive standardized questionnaire evaluating complications, therapeutics, and outcomes regarding BCG vaccination in patients given a diagnosis of SCID was widely distributed. Summary statistics and association analysis was performed. Results Data on 349 BCG-vaccinated patients with SCID from 28 centers in 17 countries were analyzed. Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications ( P = .006) and death caused by BCG-associated complications ( P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/μL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/μL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection ( P < .0001). Conclusions BCG vaccine has a very high rate of complications in patients with SCID, which increase morbidity and mortality rates. Until safer and more efficient antituberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications.
The identified FOXP3 gene mutation was associated with a reduced protein expression in Treg cells (Figs E1 and E2 available in this article's Online Repository at www.jacionline.org). ...at 6 months ...of age, he received an unmanipulated, unrelated donor cord blood stem cell transplant (1 DP mismatch) with sub-myeloablative conditioning and graft-versus-host disease (GvHD) prophylaxis (see this article's Methods section and Fig E3 in the Online Repository at www.jacionline.org). Consistent with the sub-myeloablative conditioning regimen the patient has received, mixed myeloid chimerism was also observed; however, as previously reported,4-6 donor myeloid chimerism is not necessary to control the disease. ...FOXP3 protein expression by Treg cells increased over time (Fig E2).
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