Our studies of adult immune reconstitution have demonstrated that severe deficits in naive T cells and TCR repertoire develop and persist in older patients with limited renewal of thymopoiesis. In order to develop IL-7 as a potential therapeutic agent to enhance nave populations in these patients, we initiated the first phase I study of recombinant human IL-7 (rhIL-7) administration in humans. We demonstrated that two weeks of alternate day treatment with rhIL-7 produced a marked dose-dependent increase in the numbers of circulating CD4+ and CD8+ T cells that persisted in follow-up assays at 6 to 12 weeks post treatment.14,15 Furthermore, rhIL-7 therapy disproportionately increased CCR7+CD27+CD45RA+ naive and CCR7+CD27+CD45RA- central memory cells, which represent the most diverse components of the mature TCR pool, at the expense of the CCR7-CD27-CD45RA+/- effector populations. The proportion of naive cells in the total CD8+ population increased by as much as 39%. We further documented that IL-7 produced a prolonged period of cellular expansion (Ki67+ ) and elevation of anti-apoptotic factors (Bcl-2) in naive and memory T cells, but not in effector T cells. Part of the basis for this disparity is the relatively low expression of the IL-7R(CD127) in effector T cells, particularly CD8 effectors. Similarly Treg cells, which have low expression of IL-7R, did not show the same sharp increase in the percentage of cells in cycle following initiation of IL-7 therapy and declined as a percentage of the total CD4 population. Because of the extent of this population shift, we hypothesized that IL-7 would lead to an overall increase in TCR diversity in CD4+ and CD8+ T-cells. We assessed TCR diversity using spectratype analysis on sorted CD4 and CD8 populations at day 0 and one week after rhIL-7 therapy (day 21) in six subjects. Three of these subjects were over 60 years of age, and a fourth patient was severely T cell deficient following recent chemotherapy. For each patient, we compared pre- and post-therapy spectratype divergence from a Gaussian-like normal donor standard. The global diversity (divergence from a normal donor standard in each of 22 BV families) of pre and post spectratypes was compared by Wilcoxon paired non-parametric analysis. We determined that 4 of the 6 subjects had a statistically significant increase (P <.05) in repertoire diversity following IL-7 treatment, as compared to baseline, in either the CD4+, CD8+, or both T-cell populations. This expansion of nave and central memory T cells and the disproportional loss in effector cells was particularly evident in CD8 populations in which 5/6 patients had either a significant shift or a strong trend toward increased repertoire diversity. Given the short duration of therapy, the advanced ages of some patients, and the PCR-assessed decline in the frequency of TREC in even the most nave T cells (sorted CD31+CD45RA+ CD4 cells) that we observed, this enhancement in diversity was due primarily to differential population expansion, not IL-7 induced thymic output. We have thus shown that rhIL-7 has the potential to induce thymic-independent T-cell growth in naive and CM populations and enhance repertoire diversity in peripheral T-cell populations. We have also initiated a new clinical trial to treat the pulmonary complication of chronic graft versus host disease known as bronchiolitis obliterans. Preliminary results are encouraging and the study remains open and active. A new trial has also begun to treat leukemia with myeloablative therapy and assess improvement in immune reconstitution by modulation of thymus function.

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Imanguli, M M; Cowen, E W; Rose, J et al. (2014) Comparative analysis of FoxP3(+) regulatory T cells in the target tissues and blood in chronic graft versus host disease. Leukemia 28:2016-27
Williams, K M; Hnatiuk, O; Mitchell, S A et al. (2014) NHANES III equations enhance early detection and mortality prediction of bronchiolitis obliterans syndrome after hematopoietic SCT. Bone Marrow Transplant 49:561-6
Bassim, C W; Fassil, H; Mays, J W et al. (2014) Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures. Bone Marrow Transplant 49:116-21
Baird, Kristin; Steinberg, Seth M; Grkovic, Lana et al. (2013) National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis. Biol Blood Marrow Transplant 19:632-9
Foglietta, M; Neelapu, S S; Kwak, L W et al. (2013) Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients. Bone Marrow Transplant 48:269-77
Fowler, Daniel H; Mossoba, Miriam E; Steinberg, Seth M et al. (2013) Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood 121:2864-74
Hardy, Nancy M; Fellowes, Vicki; Rose, Jeremy J et al. (2012) Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation. Blood 119:2956-9
Tomblyn, M; Chen, M; Kukreja, M et al. (2012) No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation. Transpl Infect Dis 14:468-78
Salit, Rachel B; Fowler, Daniel H; Wilson, Wyndham H et al. (2012) Dose-adjusted EPOCH-rituximab combined with fludarabine provides an effective bridge to reduced-intensity allogeneic hematopoietic stem-cell transplantation in patients with lymphoid malignancies. J Clin Oncol 30:830-6
Fassil, H; Bassim, C W; Mays, J et al. (2012) Oral chronic graft-vs.-host disease characterization using the NIH scale. J Dent Res 91:45S-51S

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