Retarded recovery of functional T cell frequencies in T cell-depleted bone marrow transplant recipients

Daley, John P.; Rozans, Marta K.; Smith, Brian R.; Burakoff, Steven J.; Rappeport, Joel M.; Miller, Richard A.

doi:10.1182/blood.v70.4.960.960

Cited by 44 publications

(9 citation statements)

References 18 publications

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“…Furthermore, the monkeys used in the prior safety studies had intact bone marrow and lymphoid function whereas the animals in our studies were recipients of autologous grafts from which the T cells had been removed. T cell depletion from marrow grafts is known to delay restoration of T cell-dependent immune functions in transplant recipients (39). We surmise that severe immunosuppression was important in disease pathogenesis.…”

Section: Discussionmentioning

confidence: 92%

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer.

Donahue

Kessler

Bodine

et al. 1992

The Journal of Experimental Medicine

512

217

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Moloney Murine Leukemia Virus (MoMuLV) causes T cell neoplasms in rodents but is not known to be a pathogen in primates. The core protein and enzyme genes of the MoMuLV genome together with an amphotropic envelope gene are utilized to engineer the cell lines that generate retroviral vectors for use in current human gene therapy applications. We developed a producer clone that generates a very high concentration of retroviral vector particles to optimize conditions for gene insertion into pluripotent hematopoietic stem cells. This producer cell line also generates a much lower concentration of replication-competent virus that arose through recombination. Stem cells from rhesus monkeys were purified by immunoselection with an anti-CD34 antibody, incubated in vitro for 80-86 h in the presence of retroviral vector particles with accompanying replication-competent virus and used to reconstitute recipients whose bone marrow had been ablated by total body irradiation. The retroviral vector genome was detected in circulating cells of five of eight transplant recipients of CD34+ cells and in the circulating cells of two recipients of infected, unfractionated bone marrow mononuclear cells. Three recipients of CD34+ cells had a productive infection with replication-competent virus. Six or seven mo after transplantation, each of these animals developed a rapidly progressive T cell neoplasm involving the thymus, lymph nodes, liver, spleen, and bone marrow. Lymphoma cells contained 10-50 copies of the replication-competent virus, but lacked the retroviral vector genome. We conclude that replication-competent viruses arising from producer cells making retroviral vectors can be pathogenic in primates, which underscores the importance of carefully screening retroviral producer clones used in human trials to exclude contamination with replication-competent virus.

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Section: Discussionmentioning

confidence: 92%

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer.

Donahue

Kessler

Bodine

et al. 1992

The Journal of Experimental Medicine

512

217

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“…B-cell as well as T-cell recovery is probably functional, as normal levels of IgM and IgA and a normal response of lymphocytes to T-and B-cell mitogens have been demonstrated after CBT (Locatelli et al, 1996;Abu-Ghosh et al, 1999;Knutsen & Wall, 1999;Thomson et al, 2000). Most data on immune reconstitution after stem cell transplantation in children are on TCD bone marrow grafts (Cowan et al, 1987;Daley et al, 1987;Foot et al, 1993;Kook et al, 1996;Small et al, 1999). The detailed analysis of Kook et al (1996) on immune reconstitution after TCD BMT in 102 children reported normalization (defined as .…”

Section: Discussionmentioning

confidence: 99%

Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children – a Eurocord analysis

Niehues¹,

Rocha

Filipovich³

et al. 2001

Br J Haematol

119

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Immune recovery after cord blood transplantation (CBT) is of concern owing to the low number of lymphocytes transferred with the graft and their immaturity. Risk factors influencing lymphocyte subset reconstitution related to disease, patient, donor and transplant were studied in 63 children (< 16 years), given either related (n = 14) or unrelated (n = 49) CBT for malignant (n = 33) or non‐malignant diseases (n = 30). Only children with sustained myeloid engraftment were analysed. Absolute numbers of T (CD3+, CD4+, CD8+), B and natural killer (NK) cells were reported 2–3, 6, 9, 12 and 12–24 months after CBT. Median patient age was 4·0 years (0–15) and median follow‐up was 23 months (1·7–61·0). Twenty‐six patients received human leucocyte antigen (HLA)‐matched CBT and 37 received HLA‐mismatched CBT. The median number of nucleated cells (NCs) collected/recipient weight was 6·1 × 107/kg. In this selected population, the estimate 2 year survival was 85%. Lymphocyte reconstitution (defined as the median time to reach the normal value of age‐matched healthy children) was 3, 6 and 8 months for NK, B and CD8+ cells, while it was 11·7 months for both CD3+ and CD4+ lymphocytes. In the multivariate analysis, factors favouring T‐cell recovery were: related donor (P = 0·002); higher NCs/kg (P = 0·005) and recipient cytomegalovirus (CMV)‐positive serology (P = 0·04). Presence of acute graft‐versus‐host disease (GVHD) delayed T‐cell recovery (P = 0·04). To summarize, in children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by our results.

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“…Moreover, the diversity of the TCR repertoire has been shown to be greater in the recipients of unmanipulated grafts than in the recipients of T‐cell‐depleted grafts (Roux et al , 1996). Conversely, T‐cell recovery is delayed for a period exceeding 18 months after allogeneic T‐cell‐depleted BMT (Kook et al , 1996), as compared with undepleted BMT (Janossy et al , 1986; Daley et al , 1987). Positive selection of CD34 + cells, introduced to deplete tumour cells, has also been shown to be an efficient procedure for T‐cell depletion, achieving an approximately 3‐log reduction of T cells in PBSC collections (Bensinger et al , 1996; Finke et al , 1996; Link et al , 1996; Urbano‐Ispizula et al , 1997).…”

Section: Discussionmentioning

confidence: 99%

Poor lymphocyte recovery following CD34‐selected autologous peripheral blood stem cell transplantation for non‐Hodgkin's lymphoma

Diviné¹,

Boutolleau²,

Delfau‐Larue³

et al. 1999

Br J Haematol

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Positive selection of CD34+ cells in autologous grafts, designed to deplete tumour cells, also results in T-cell depletion. To assess the reconstitution of the different lymphocyte subsets and of the T-cell repertoire diversity following autologous transplantation of selected CD34+ peripheral blood stem cells (PBSC), we analysed sequential blood samples in eight patients autografted for advanced B-cell non-Hodgkin's lymphoma in a phase I-II pilot study. Although natural killer cell recovery was rapid, T- and B-cell recovery was delayed with a median of 110/microliters CD4+, 175/microliters CD8+ T cells and 45/microliters B cells at 12 months post-transplant. The naive CD45RA+ T-cell compartment was profoundly deficient up to 12 months for both CD4+ and CD8+ subsets. A transient expansion of memory CD8+CD45RO+ T cells consisting of an increased percentage of CD57+CD28- cells occurred within the first 3 months post-transplant, but the memory CD4+CD45RO+ T cells remained far below the normal value. The CD8+CD28+ T-cell subset did not recover. Using multiplex PCR analysis of the T-cell receptor gamma locus, we found that the repertoire diversity improved at 12 months after being poor and oligoclonal during the first 3 months post-transplant. As shown by monoplex PCRgamma analysis of every VJ combination, despite T-cell depletion of the graft, mature T cells were carried over with the selected CD34+ PBSC and contributed to the T-cell recovery after transplantation.

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Retarded recovery of functional T cell frequencies in T cell-depleted bone marrow transplant recipients

Cited by 44 publications

References 18 publications

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer.

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer.

Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children – a Eurocord analysis

Poor lymphocyte recovery following CD34‐selected autologous peripheral blood stem cell transplantation for non‐Hodgkin's lymphoma

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