Allogeneic peripheral stem cell transplantation using positively selected CD34+ cells from HLA-mismatched donors

Abstract

Summary:and a preserved host immune system. Data on the effect of HLA mismatching on the incidence of graft failure showed We examined five children who underwent allogeneic an overall increase in the incidence in the mismatched peripheral stem cell transplantation (PSCT) using posigroup compared to HLA-identical sibling bone marrow tively selected CD34 ؉ cells from three or two loci-mistransplantation (BMT) and the frequency of graft failure matched donors. CD34 ؉ cells mobilized from peripheral increased as donor/recipient HLA disparity increased. 3,4 blood were separated by immunomagnetic beads.While the host immune system is defeated by T cells con-CD34 ؉ cells at 2.2-6.2 ؋ 10 6 /kg were transplanted into tained in the grafts, in the case of SCT with T cell-depleted three patients with refractory leukemia, a patient with grafts, immune competent cells in recipients are preserved. relapsed medulloblastoma and a patient with Fanconi's In the mouse model, the immunologic rejection of T cellanemia following a conditioning regimen which depleted histoincompatible BMT can be overcome by included irradiation, alkylating agents and antithymoincreasing the doses of irradiation or by adding selective cyte globulin treatment. The number of infused CD3 ؉ measures with minimal toxicity, such as splenic irradiation cells included in grafts was 2.3-22.7 ؋ 10 4 /kg. Four or in vivo treatment with anti-T cell monoclonal antibodies, patients achieved engraftment and hematopoietic reconto the conditioning regimen. 5-7 However, previous results stitution (Ͼ5 ؋ 10 8 /l of neutrophils on day 10 or 11).of clinical trials using these procedures have not been satisGraft rejection was observed in the patient with Fanfactory. 8,9 Another means of overcoming graft failure is to coni's anemia, but a rapid engraftment was obtained increase the number of stem cells in the graft. This has been after second PSCT. Although no prophylactic agents found to be the case in studies investigating the relationship other than ATG (included in the conditioning regimen) between transfused cell doses and the incidence of rejecwere used, greater than grade I acute GVHD was not tion. 10 Recently, successful engraftment using positively observed, but limited chronic GVHD was observed in selected allogeneic CD34 + bone marrow cells from two or two patients. The two patients with leukemia relapsed three loci-mismatched donors was reported. This procedure on days 103 and 210, respectively, and the patient with enables a larger number of transplantable stem cells. 11,12 medulloblastoma died of disease on day 159. The patientThe administration of recombinant human granulocyte with Fanconi's anemia died of fungal infection. CMV colony-stimulating factor (rhG-CSF) can mobilize a sufand HHV-6 diseases developed in four and two patients, ficient number of peripheral stem cells (PSCs) to permit respectively. Thus, although SCT using positively selecthe collection of a transplant inoculum. Infusion of these ted peripheral CD34 ؉ cells may be an alternative cytokine-...

Effective T cell regeneration following high-dose chemotherapy rescued with CD34+ cell enriched peripheral blood progenitor cells in children

“…Takaue et al 36 investigated 41 children with leukaemia and NHL after unsorted autologous PBPC transplantation and showed abnormally low CD4 + counts and an inverse CD4/CD8 ratio for Ͼ12 months after treatment. Matsuda et al 15 reported five children having undergone CD34 + selected PBPC transplantation from allogeneic mismatched donors. The CD3 + cell counts remained low through the observation time of a maximum of 210 days after transplantion with CD4 + cells being more severely depressed than CD8 + cells.…”

“…CMV infection is known to abrogate a successful T cell regeneration, as exemplified in one patient after CD34 + selected PBSC transplantation. 15 Third, the dose of CD34 + cells was high (median 7.1 × 10 6 CD34 + cells/kg). It has been shown that the period of time required for leukocytic and thrombocytic recovery after PBPC rescue is linked to the number of CD34 + cells used as a rescue.…”

“…Since previous evidence suggests that peripheral T cells reinfused together with bone marrow or PBPC significantly contribute to the reconstitution of T cells after myeloablative treatment, [11][12][13] T cell depletion may adversely affect T cell regeneration. 14 Recent reports of the kinetics of lymphoid reconstitution after CD34 + selected autologous and allogeneic PBPC transplantation in children and adults 15,16 showed that T cell reconstitution was delayed as compared to a rescue with unmanipulated grafts. We hypothesised that high residual thymic activity, as present in early childhood, might allow for a rapid regeneration of T cells in the absence of suppressive factors, such as GVHD, and studied T cell regeneration in four paediatric patients after autologous CD34 + selected PBPC transplantation.…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…Table 3 shows a summary of pretransplant conditioning and GVHD prophylaxis regimens used for HLA-haploidentical donor transplantation in Japan. Infusion of purified CD34-positive cells from bone marrow [95] or peripheral blood mononuclear cells [96,97] after ATG-containing preconditioning has been studied in Japan as well, with a low incidence of acute GVHD.…”

Antitumor effect of allogeneic hematopoietic SCT in metastatic medulloblastoma

“…1,2 Few data are currently available in this field in patients with medulloblastoma. Matsuda et al 3 reported one child who obtained a short-lasting PR following allogeneic hematopoietic SCT for relapsed medulloblastoma. Lundberg et al 4 reported one patient who achieved CR lasting more than 2 years following allogeneic hematopoietic SCT for recurrent metastatic medulloblastoma.…”