Relationship between patterns of engraftment in peripheral blood and immune reconstitution after allogeneic bone marrow transplantation for (severe) combined immunodeficiency

Abstract

We report the outcome of allogeneic bone marrow transplantation (BMT) as treatment for severe combined immunodeficiency disease (SCID) in 31 patients grafted from 1968 until 1992. The patients received a graft from an HLA-identical related (n = 10), an HLA-haplo-identical related (n = 19), or a closely HLA-matched unrelated (n = 2) donor that resulted in the long-term survival of 6 of 10, 9 of 19, and 0 of 2 children, respectively. Major complications included failure of engraftment and early death caused by respiratory failure. The chimerism pattern and immunologic reconstitution were evaluated in 15 children who survived more than 1 year with sustained engraftment. The pattern of engraftment was investigated within flow-sorted peripheral blood (PB) T- and B-lymphoid, natural killer (NK), and myelomonocytic cell populations using the amplification of variable number of tandem repeats by the polymerase chain reaction. The immunologic reconstitution was assessed by various in vitro and in vivo parameters. Although the number of PB T cells and the in vitro T-cell proliferative response was in the lower region of normal in the majority of cases and even subnormal in some, in all cases donor T-cell engraftment and reconstitution of T-cell immunity was observed. Residual host-type T cells (1% to 5%) were detected in eight cases at multiple occasions. All children showed normal serum IgM and IgG subclass levels and produced specific IgG antibodies after vaccination, irrespective of donor B-cell engraftment. However, three HLA haplo-identical graft recipients with host-type B lymphoid and myeloid cells have a persistent selective IgA deficiency. NK cells were either of donor, host, or mixed origin. Donor NK cell engraftment restored defective in vitro NK cell function of the recipient. We conclude that determination of lineage-specific engraftment patterns provides valuable information for the understanding of the immunologic reconstitution after allogeneic BMT for SCID.

Intrinsic defects of B cell function in X-linked severe combined immunodeficiency

“…In a recent report of 34 unconditioned transplantations for X-SCID from both HLA-identical and non-HLAidentical donors, 27 (˚80 %) patients remained on Ig substitution [10]. The suggestion that the continued presence of host + c-defective B cells might result in residual humoral defects has been considered by this and a number of previous reports [9,12,15]. However, 20 % of the patients in the study by Buckley et al [10] and significant numbers in other reports [12,14,16] had normal B cell function.…”

“…Typically after non-conditioned transplantation, the B cell pool is largely host derived [10,12], although little is known about the absolute distribution of class-switched cells between donor and host populations. Considering the data in Fig.…”

“…The survival following HSCT for all forms of SCID is now over 90 % when a genotypically matched donor is available [9] and between 50 % and 80 % following non-HLA-identical transplantation from parents or unrelated volunteer donors [9][10][11][12]. Despite these encouraging survival figures, a significant number of patients continue to have poor humoral immune function after both HLA-identical and non-HLA-identical bone marrow transplantation [10,[12][13][14] and require lifelong Ig therapy. The reasons for continued immune dysfunction are poorly understood and may be due to the degree of HLA compatibility of the graft or the extent of donor B cell chimerism.…”

Gene therapy of severe combined immunodeficiencies

“…Residual graft versus host disease and, most importantly, delay to immune function development account for the majority of deaths. New T-cell development requires a 3-4 month minimal period, and sometimes more, to occur (1)(2)(3)(4)(5). In addition, in a minority of patients, T-cell functions remain partially defective in the long term, while in the majority B-cell function does not develop (1,2), necessitating intravenous (IV) immunoglobulin substitution for life.…”

B‐cell‐mediated Graft‐versus‐host Disease in Transplantation

“…Graft 6 lymphocytes can also be beneficial in bone marrow transplantation. Patients with severe combined immunodeficiency usually develop donor B cells after transplantation [27]. Other marrow transplant patients also acquire donor antibodies [28].…”