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 showed that rhIL-7 has the potential to induce thymic-independent T-cell expansion in naive and CM populations and enhance repertoire diversity in peripheral T-cell populations. Whether this repair of repertoire is of functional importance is being addressed in a new clinical trial which is no longer delayed pending a source of clinical grade IL-7. A new source has been identified and a new study is being written with near completion of the final draft. We also initiated a clinical trial to treat the pulmonary complication of chronic graft versus host disease known as bronchiolitis obliterans. Results were encouraging and led to a national multi-center trial. Together, the results have changed the general care of patients with this pulmonary complication of allogeneic transplant. A trial treating leukemia with myeloablative therapy and assessing improvement in immune reconstitution by modulation of thymus function by temporary blockade of androgen signaling is completed with lab results under study. In a trial involving unrelated donor allogeneic peripheral blood stem cell transplantation, we have developed an extensive, clinically annotated data base of laboratory values relevant to immune reconstitution. This data set has shown that steroid therapy has little immediate effect on T cell numbers and confirms our data on expansion of CD8+ T cells associated with CMV infection. We have used cells and tissue biopsies from this trial to prospectively study the pathogenesis of chronic graft-versus host disease and found that it a Type I driven (not Type II as has been thought) process. These results are now published. We are seeking new therapies for this complication of allogeneic transplant based on this new understanding. At this point it appears that introduction of such therapy may await approval of such agents for other indications. In another trial assessing the feasibility of imaging the hematopoietic stem cell compartment during engraftment, it was found that such imaging is feasible and also quantifiable, so that applicability to settings of radiation injury may be possible. That is, subjects of such injury may be identified as needing intervention with hematopoietic stem cell rescue or not.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010960-11
Application #
9779755
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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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