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 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. These data were published in 2009 (Sportes et al 2009). 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 data were incorporated into a report on the clinical effects of IL-7 therapy in 2010 (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, 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 CGVHD following allogeneic transplantation have been evaluated by a multidisciplinary clinical team. The PSC core has supported the study by contributing to the identification of CGVHD biomarkers and the understanding of CGVHD 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 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 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). Concurrently, we observed increased expression of interferon (IFN)-induced factors including MxA (evidence of Type I IFN), the chemokine MIG (CXCL9) and IL-15 in the affected tissues;these factors support the migration, Th1/Tc1 differentiation and expansion of the T effectors. These data support a model that oral CGVHD results from the interaction of IFN-driven inflammatory processes and Tc1/Th1 differentiated effectors.(Published in 2009, with ongoing studies in erythematous and fibrotic CGVHD of the skin). In a third project exploring IFN-induced processes in CGVHD, 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. These studies formed the basis for an application for a Staff Scientist Innovation Award, funded in January 2010. In a fourth project, we have initiated studies into the role of regulatory T cells (Treg) in CGVHD. Treg cells, which may be involved in controlling autoimmunity, are being assessed in the circulation and in affected tissues. In addition to research on patients in the CGVHD natural history protocol, we support a therapeutic trial for bronchiolitis obliterans, a severe complication of CGVHD (P. I. Ronald Gress and Kirsten Williams: 08-C-0097). We assess leukotriene receptor (LTR) expression in leukocytes and in bronchial lavage cells to assess the role of LTR in progressive fibrosis of lung airways. 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, 08-C-0088, 07-C-0195). 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, 07-C-0195, 09-C-0210);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 Ronald Gress, 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. In collaboration with Alan Wayne and Terry Fry (01-C-0125), we have assessed the contributions of donor T cells and thymic-dependent repopulation in the recovery of T cell populations in pediatric transplant recipients. These studies demonstrate the role of T-replete transplants and reduced intensity cytoreductive regimens in producing a rapid repopulation of T cells in young recipients. Finally, when 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 treated for myeloid malignancy in the context of MonoMacs congenital immune deficiency (09-C-0096, PI: Dennis Hickstein: repopulation by donor monocyte, T, B and NK cells) and on patients receiving dual donor umbilical cord blood (09-C-0210, PI: Michael Bishop: NK chimerism.

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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
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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