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 a Phase I clinical trial of IL-7 administration (P. I. Claude Sportes: 03-C-0152), we determined that IL-7 significantly expanded naive 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 (Sportes et al 2009). We further determined that IL-7 produced a transient expansion of early B cell lymphopoiesis (Sportes et al 2010). These studies support the use of IL-7 therapy to enhance T cell numbers and repertoire in patients with limited thymopoietic capacity. A newly initiated vaccine trial (11-C-0146;P.I. Claude Sportes) assesses the effect of IL-7 on vaccine responses in older patients. The PSC supports this effort by assessing effects of a new IL-7 formulation on T and B cell populations and by assessing alterations in T cell receptor repertoire. 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. Cytokine and monokine production following based transplant regimens incorporating ex vivo expanded cytokine defined T effectors: An ongoing project has assessed lymphokine and monokine production capacity post transplant, focusing on allogeneic transplants incorporating immune therapy with Th2.rapa (P. I. Dan Fowler lymphoma and renal carcinoma: 04-C-0055, 08-C-0088) or T1/T2 donor-derived cells (P.I. Michael Bishop metastatic breast cancer: 04-C-0131). In the early post-transplant period, the cytokine and monokine production capacity of peripheral blood cells has been determined by generation of anti CD3/anti CD28-stimulated 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 extent and durability of the cytokine shift resulting from the infusion of T1/T2 or Th2-rapa cells. Immune reconstitution following lymphodepletion: In several ongoing ETIB clinical trials of allogeneic stem cell transplantation therapies (04-C-0055, 07-C-0195, 09-C-0210;09-C-0096;PIs Daniel Fowler, Michael Bishop, Steven Pavletic and Dennis Hickstein) the process of immune reconstitution has been assessed, focusing on the factors contributing to individual variation in recovery. These data have contributed to a report on the efficacy of EPOCH-F, a novel non-myeloablative induction regimen, in allogeneic stem cell transplantation in patients with multiple myeloma (Jamshed et al., 2011). We currently are using 10-color flow cytometery to characterize lymphocyte repopulation and correlate this with thymic recovery, relapse, GVHD and reactivation of chronic latent viruses. In addition, when assessment of lineage-specific repopulation is important, we work with the ETIB Flow Cytometry Core facility (William Telford) to sort lymphocytes for subset-specific donor chimerism analysis. These assays include ongoing studies on patients transplanted for monogenic immune deficiency involving GATA2 or DOCK8 (09-C-0096, PI: Dennis Hickstein) and on patients receiving dual donor umbilical cord blood (09-C-0210, PI: Michael Bishop). Finally, we have collaborated with the Hematology Branch of the NHLBI to provide analyses of T cell receptor repertoire diversity in long term recipients of allogeneic stem cell transplantation, demonstrating that recipients develop a diverse repertoire after 10 years that is comparable to the donor repertoire (Le et al., 2011). 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 CGVHD following allogeneic transplantation have been evaluated by a multidisciplinary clinical team. The PCS core has supported the study by contributing to the identification of CGVHD biomarkers and the understanding of CGVHD pathogenesis. Two studies of factors contributing to the development of sclerotic skin disease in CGVHD have been accepted (Martires et al., Blood in press;Martires et al., Archives Dermatology, in press) as well as a study of correlations of clinical laboratory tests with CGVHD prognosis (Grkovic et al., Leukemia, in press). Furthermore, we have supported a therapeutic trial for bronchiolitis obliterans, a severe complication of CGVHD (P. I. Ronald Gress and Kirsten Williams: 08-C-0097), by assessing leukotriene receptor (LTR) expression in leukocytes and in bronchial lavage cells to define the role of LTR in progressive fibrosis of lung airways. Finally, CGVHD has become a significant focus for research in the PCS core. Three PCS projects have been initiated from this study. First, we have determined that plasma levels of the cytokine BAFF are elevated in CGVHD. 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 failure in the negative selection process occurring at this maturation stage. Such a change may contribute to the autoimmune symptoms that characterize CGVHD. Second, we have initiated studies into the role of regulatory T cells (Treg) in CGVHD by characterizing Treg in the circulation and in affected. In previous analyses of affected tissues, we found that severe oral CGVHD was primarily associated with infiltrating T cells expressing T-Bet, a transcription factor marking Type I cytokine polarization (Th1/Tc1). Concurrently, we observed increased expression of IFN-induced factors that potentially support the migration, Th1/Tc1 differentiation and expansion of T effectors into these tissues. These studies support the hypothesis that IFN-induced inflammatory processes may underlie many of the systemic processes in CGVHD (Imanguli et al, 2009;Hakim, 2010). These studies formed the basis for an application for a Staff Scientist Career Development Award, funded in January 2010, This project, detailed under the Innovation Award section, used circulating monocytes as reporter cells for determining the cytokine and chemokine pathways underlying the development of the autoimmune-like symptoms of CGVHD. In coordinated studies, we have assessed plasma levels of cytokines and chemokines and have measured the gene expression patterns of sorted monocytes by microarray and quantitative multiplex RNA measurements. We determined that Type I IFN-driven processes are elevated in CGVHD patients, as compared with normal donors and with non-GVHD transplant recipients. The work may support the development of diagnostic or prognostic assays of CGVHD and contribute to new therapeutic approaches.

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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
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
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
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
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
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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