The Preclinical Service Core (PSC) projects have developed from transplantation protocols implemented by the clinical staff of ETIB. Using peripheral blood and marrow, and tumor and CGVHD tissue biopsies, we have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity and thymopoietic activity. All data are incorporated into protocol-specific spreadsheets, linking samples to protocol arms and transplant time points, and are accessible by branch clinicians over secure NIH networks. Effects of IL-7 administration: In association with a Phase I clinical trial of IL-7 administration (P. I. Claude Sportes: 03-C-0152, in collaboration with Crystal Mackall in POB), we determined that IL-7 significantly expanded nave and central memory CD4 and CD8 T cells, as compared to effector cells, resulting in a significant increase in the diversity of the overall T cell receptor repertoire. In further studies of the clinical effects of this therapy, we determined that IL-7 produced a transient expansion of early B cell lymphopoiesis that was evident in the peripheral blood as an increase in transitional (T1) immature B cells. These studies support the use of IL-7 therapy to enhance T cell numbers and repertoire in patients with limited thymopoietic capacity, such as in aging populations and in patients with immune deficits after chemotherapy. Continuing studies will focus on the role of IL-7 in conjunction with vaccine responses in older patients. Immune reconstitution following intensive lymphodepletion and autologous CD34+ stem cell transplantation in patients with severe systemic lupus erythematosus (SLE): In an ongoing trial (P.I. Steven Pavletic 04-C-0095), T and B cell immune reconstitution has been monitored to assess the efficacy of the cytoreductive regimen in depleting T and B cells and the timecourse of immune recovery. These continuing studies contribute to development of autologous transplant as a therapeutic modality in treatment of severe lupus. Immune populations and dysfunction in chronic graft vs host disease (CGVHD): In an ongoing natural history protocol (P.I. Steven Pavletic: 04-C-0281), patients who have developed chronic GVHD following allogeneic transplantation have been evaluated by a multidisciplinary clinical team. The PSC core has supported the study by contributing to the identification of biomarkers and the understanding of chronic GVHD pathogenesis. Four PCS projects have been initiated from this study. First, we have determined that plasma levels of the cytokine BAFF (B cell activating factor of the TNF family) are elevated in chronic GVHD. This increase is significantly correlated both with elevated plasma levels of Interferon (IFN)-induced inflammatory cytokines and with reduced levels of circulating B cells. We have linked these elevated BAFF levels with increases in transitional B cells, consistent with a reduction in the negative selection process occurring at this maturation stage. Such a change may contribute to the development of the autoimmune symptoms that characterize CGVHD. In a second project, Matin Imanguli, an ETIB clinical research fellow working in the Core, used immunohistochemistry and PCR to determine that severe oral CGVHD of the buccal mucosa was primarily associated with infiltrating T cells expressing T-bet, a transcription factor marking Type I cytokine polarization (Th1/Tc1). Increased epithelial apoptosis, the distinctive feature of active oral CGVHD, was associated with an increase in CD8 cells with cytotoxic markers. Concurrently, we observed increased expression of interferon-induced factors including the chemokine MIG (CXCL9) and IL-15 in both infiltrating cells and keratinocytes in the affected tissues;these factors support the migration, Th1/Tc1 differentiation and expansion of the T effectors. We further observed the Type I interferon-specific gene MxA in the mucosal epithelium and plasmacytoid dendritic cells (pDC), the main producer of Type I interferons, in the infiltrate. These data support a model that oral cGVHD results from the interaction of interferon-driven inflammatory processes and Tc1/Th1 differentiated effectors. In a third project exploring IFN-induced processes in CGVHD, we have identified a similar process of infiltration of cytotoxic T effectors in the dermis in patients with erythematous cutaneous CGVHD. Again, the IFN induced chemokine MIG is produced by affected keratinocytes and infiltrating myeloid cells. We have further correlated these findings in severely affected patients with elevated levels of IFN-induced cytokines and chemokines in the patients plasma. These three studies support the hypothesis that IFN-induced inflammatory processes may underlie many of the systemic processes in CGVHD. In a fourth project, we have initiated studies into the role of regulatory T cells (Treg) in CGVHD. Treg cells have been proposed to play a critical role in controlling autoimmunity. We have characterized Treg in the circulation and in affected tissues, investigating the roles of thymopoiesis, proliferative expansion and chemokine-controlled trafficking in Treg distribution. In addition to research on patients in the CGVHD natural history protocol, we support a therapeutic trial for bronchiolitis obliterans, a severe complication of chronic GVHD (P. I. Ronald Gress and Kirsten Williams: 08-C-0097). The core provides multi-parameter flow cytometric assessment of leukotriene receptor levels in peripheral blood leukocytes and in bronchial lavage cells to support a trial of the efficacy of a drug blocking the leukotriene pathway in inhibiting the progression of fibrosis in this obstructive lung disorder. Cytokine and monokine production following Th2 and Th2/Tc2 therapy based transplant regimens: An ongoing project has assessed lymphokine and monokine production capacity post transplant, focusing on allogeneic transplants incorporating immune therapy with Th2, Th2/Tc2 or Th2.rapa donor-derived cells (P. I. Dan Fowler, 04-C-0055, 04-C-0131). In the early post-transplant period and at regular intervals thereafter, the cytokine and monokine production capacity of peripheral blood cells has been determined by generation of anti CD3/anti CD28-stimulated and bacterial lipopolysaccharide (LPS) stimulated supernatants and by the assessment of the frequencies of cytokine producing T cells by flow cytometry. These assays support these protocols by evaluating the efficacy and durability of the cytokine shift resulting from the infusion of Th2/Tc2 and Th2-rapa cells. Immune reconstitution following lymphodepletion: In several ongoing ETIB clinical trials of allogeneic and autologous stem cell transplantation therapies (04-C-0055 and 07-C-0195;PIs Daniel Fowler and Michael Bishop) as well as in continuing follow-up of earlier trials (96-C-0104, 99-C-0143, 03-C-0077;P.I.s Claude Sportes, Daniel Fowler, Michael Bishop), the process of immune reconstitution has been assessed, focusing on the contributions of thymopoiesis and homeostatic cytokines to the recovery of CD4 and CD8 T cell populations following transplantation. These studies have demonstrated an inverse correlation between circulating plasma levels of IL-7 and CD4 and CD8 T cell populations. Furthermore, (in collaboration with T. Fry in POB) they have identified IL-7 levels at 2 weeks post transplant as a potential biomarker predictive of development of acute GVHD. Finally, in collaboration with Alan Wayne and Terry Fry (01-C-0125), we have assessed the contributions of donor [summary truncated at 7800 characters]

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Poe, Jonathan C; Jia, Wei; Su, Hsuan et al. (2017) An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. Blood 130:2131-2145
Cooke, Kenneth R; Luznik, Leo; Sarantopoulos, Stefanie et al. (2017) The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:211-234
Hakim, Frances T; Memon, Sarfraz; Jin, Ping et al. (2016) Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease. J Immunol 197:3490-3503
Pirsl, Filip; Curtis, Lauren M; Steinberg, Seth M et al. (2016) Characterization and Risk Factor Analysis of Osteoporosis in a Large Cohort of Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 22:1517-1524
Amarnath, Shoba; Foley, Jason E; Farthing, Don E et al. (2015) Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo. Stem Cells 33:1200-12
Paczesny, Sophie; Hakim, Frances T; Pidala, Joseph et al. (2015) National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report. Biol Blood Marrow Transplant 21:780-92
Mossoba, Miriam E; Halverson, David C; Kurlander, Roger et al. (2015) High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. Clin Cancer Res 21:4312-20
Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2014) Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood 124:1450-9
Grossman, Jennifer; Cuellar-Rodriguez, Jennifer; Gea-Banacloche, Juan et al. (2014) Nonmyeloablative allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Biol Blood Marrow Transplant 20:1940-8
Salit, Rachel B; Fowler, Daniel H; Dean, Robert M et al. (2013) Host lymphocyte depletion as a strategy to facilitate early full donor chimerism after reduced-intensity allogeneic stem cell transplantation. Biol Blood Marrow Transplant 19:1509-13

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