YEARS

-

AUTHORS

Frances Hakim

TITLE

Immune reconstitution following autologous and allogeneic stem cell transplant

ABSTRACT

The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols implemented by the clinical staff of ETIB. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from ongoing ETIB protocols are processed and preserved by the core facility. We have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity, and gene expression to support research studies of clinical protocols. 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. These on-going studies involve analysis of ETIB trials that include non-myeloablative reduced intensity allogeneic HSCT for lymphoma using sibling and matched-unrelated donors, autologous transplantation for myeloma and for systemic autoimmunity, and myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). In the past year, these immune monitoring studies have contributed to reports on allogeneic HSCT in lymphoma and renal carcinoma involving novel lymphodepletion regimens and utilization of adoptive transfer of T-RAPA cells (Fowler et al, Clin Cancer Res, 2015). We also have supported ongoing studies of lineage-specific immune reconstitution in patients transplanted for monogenic immune deficiencies (such as GATA2 or DOCK8) (09-C-0096, 10-C-0174, PI: Dennis Hickstein (ETIB)) by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism, and to monitor repopulation of deficient lineages after allogeneic transplant (Grossman et al, Biol Blood Marrow Transpl, 2014). This past year we have been completing immune reconstitution analysis of a matched unrelated donor allogeneic transplant trial comparing two distinct regimens of GVHD prophylaxis, one dependent on antibody-mediated depletion of donor lymphocytes following transplant, the second dependent on immune suppressive agents. We determined that lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers for the first year compared to that in patients with immune suppression alone. Naive T cell populations, in particular, were severely reduced. Consistent with loss of naive cells, we determined that the overall T cell receptor repertoire diversity in the lympho-depleted arm was significantly reduced. The lymphocyte repopulation differences between the two arms correlated with significant differences in early viral infections, relapse and chronic GVHD. We also have participated in collaborative studies with Arya Biragyn (NIA) that demonstrated that activated B cells in aged adults and in post-autologous transplant patients support increased differentiation of cytotoxic CD8 effector cells, contributing to persistent immune activation in aging and after transplant (Lee-Chang et al, Blood, 2014). Chronic graft vs host disease (CGVHD), the principle cause of non-relapse morbidity and mortality after allogeneic transplantation, is a major focus for research in the PDCMF core. We have supported the efforts of the multidisciplinary CGVHD clinical team in an ongoing natural history protocol of CGVHD (P.I. Steven Pavletic: 04-C-0281) by characterizing immunologic changes of CGVHD. Furthermore, we have supported four therapeutic trials for CGVHD patient populations: (1) We have assessed expression of leukotriene receptors (LTR) in leukocytes and CRTH2 receptors on T cells and in blood and bronchial lavage fluids to define the role of Th2 lineage T cells and leukotriences in progressive fibrosis of lung airways in patients developing bronchiolitis obliterans, a severe complication of CGVHD (08-C-0097: P. I. Ronald Gress and Kirsten Williams). (2) We have assessed the effect of Imatinib, aTGFbeta signaling inhibitor, on Th17 and Treg populations, as part of a collaborative trial testing Imatinib therapy on sclerotic cutantaneous CGVHD (Dermatology and Pediatric Branch, protocol 08-C-0148, P.I. Edward Cowen and Kristin Baird)(Baird et al, Biol Blood Marrow Transpl, 2015). (3) We are analyzing changes in inflammatory gene expression in a trial of Pomalidomide (12-C-0197; P.I. Steven Pavletic) to assess efficacy against fibrosis in CGVHD patients. (4) Finally we have supported a trial of topical therapy for severe oral CGVHD (12-C-0068; P.I. Steven Pavletic/Jacqueline Mays). This extensive experience in immunologic characterization of CGVHD has also supported our participation in the CGVHD consensus report on CGVHD biomarker studies (Paczesny et al, Biol Blood Marrow Transpl, 2015). As part of our studies of the pathogenesis of CGVHD, we have characterized regulatory T cells in CGVHD through coordinated studies of blood and tissue. These studies determined that FoxP3+ regulatory T cells (Treg) increased in proportion to T effectors in tissue infiltrates in oral and cutaneous lichenoid cGVHD. Both T effector and FoxP3+ Treg cells expressed Tbet and the chemokine receptor CXCR3, consistent with a common mechanism of chemokine-mediated migration into tissue. These studies also demonstrated the presence of Treg expressing Furthermore, functional markers (ICOS and CD39) in both blood and in cGVHD target tissues. The 'activated' CD45RA-FoxP3hi subset of Treg cells, which highly expresses functional markers, was found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg functional capacity in cGVHD, and support efforts to expand Treg cells in vivo as therapy. (Imanguli et al, Leukemia 2014) In studies of CGVHD pathogenesis, we profiled gene expression of circulating monocytes in CGVHD patients, to use these cells as in situ reporter cells for systemic cytokine patterns in order to test the hypothesis that Interferon (IFN)-induced inflammatory processes may underlie many of the systemic processes in CGVHD (Imanguli et al, 2009; Hakim, 2010). Based on microarray analysis and confirmed by multiplex RNA assessments (supported by an NCI Staff Scientist Career Development Award), we determined that pathways induced by IFN were consistently upregulated across a broad spectrum of CGVHD patients, both those with severe inflammatory infiltrates in tissue and those with widespread sclerotic involvement. IFN-inducible genes, including ones specifically induced by type I IFN, were upregulated in parallel at the time of onset of CGVHD, and were reduced during treatment and after resolution of CGVHD symptoms. In addition, we found a consistent upregulation of receptor genes from the innate immune TLR/NLR/CLR pathways; these pathways are triggered by debris from dead cells to stimulate phagocytosis, induce IFNa production, and form inflammasomes. Many of these receptors are also inducible by IFN, consistent with a self-reinforcing inflammatory process sustaining CGVHD. These interlocking assessments, performed on a broad spectrum of patients severely affected with CGVHD, support a new model for the initiation and persistence of CGVHD. This model defines CGVHD as a disorder of inflammation-driven immune dysregulation and these results support a new range of options for therapy of CGVHD through interdiction of interferon pathways.

FUNDED PUBLICATIONS

  • Nonmyeloablative allogeneic hematopoietic stem cell transplantation for GATA2 deficiency.
  • Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity.
  • Dose-adjusted EPOCH-rituximab combined with fludarabine provides an effective bridge to reduced-intensity allogeneic hematopoietic stem-cell transplantation in patients with lymphoid malignancies.
  • Salivary gland involvement in chronic graft-versus-host disease: prevalence, clinical significance, and recommendations for evaluation.
  • Evolution of the donor T-cell repertoire in recipients in the second decade after allogeneic stem cell transplantation.
  • Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease.
  • Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.
  • 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.
  • Association of serum interleukin-7 levels with the development of acute graft-versus-host disease.
  • Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity.
  • Quantum dots thermal stability improves simultaneous phenotype-specific telomere length measurement by FISH-flow cytometry.
  • The thymus and the immune system: layered levels of control.
  • Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.
  • Phase I trial of adoptive cell transfer with mixed-profile type-I/type-II allogeneic T cells for metastatic breast cancer.
  • B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.
  • Host lymphocyte depletion as a strategy to facilitate early full donor chimerism after reduced-intensity allogeneic stem cell transplantation.
  • Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation.
  • High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses.
  • EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT.
  • Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa.
  • Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity
  • TRECing long-term success in SCID.
  • EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT
  • Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy.
  • Oral chronic graft-vs.-host disease characterization using the NIH scale.
  • Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses.
  • Up-regulation of NK cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 levels.
  • Quantitative analysis of T cell receptor diversity in clinical samples of human peripheral blood.
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    42 TRIPLES      14 PREDICATES      43 URIs      7 LITERALS

    Subject Predicate Object
    1 grants:af06e63143bf82f28d8a2312a4a8f985 sg:abstract The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols implemented by the clinical staff of ETIB. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from ongoing ETIB protocols are processed and preserved by the core facility. We have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity, and gene expression to support research studies of clinical protocols. 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. These on-going studies involve analysis of ETIB trials that include non-myeloablative reduced intensity allogeneic HSCT for lymphoma using sibling and matched-unrelated donors, autologous transplantation for myeloma and for systemic autoimmunity, and myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). In the past year, these immune monitoring studies have contributed to reports on allogeneic HSCT in lymphoma and renal carcinoma involving novel lymphodepletion regimens and utilization of adoptive transfer of T-RAPA cells (Fowler et al, Clin Cancer Res, 2015). We also have supported ongoing studies of lineage-specific immune reconstitution in patients transplanted for monogenic immune deficiencies (such as GATA2 or DOCK8) (09-C-0096, 10-C-0174, PI: Dennis Hickstein (ETIB)) by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism, and to monitor repopulation of deficient lineages after allogeneic transplant (Grossman et al, Biol Blood Marrow Transpl, 2014). This past year we have been completing immune reconstitution analysis of a matched unrelated donor allogeneic transplant trial comparing two distinct regimens of GVHD prophylaxis, one dependent on antibody-mediated depletion of donor lymphocytes following transplant, the second dependent on immune suppressive agents. We determined that lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers for the first year compared to that in patients with immune suppression alone. Naive T cell populations, in particular, were severely reduced. Consistent with loss of naive cells, we determined that the overall T cell receptor repertoire diversity in the lympho-depleted arm was significantly reduced. The lymphocyte repopulation differences between the two arms correlated with significant differences in early viral infections, relapse and chronic GVHD. We also have participated in collaborative studies with Arya Biragyn (NIA) that demonstrated that activated B cells in aged adults and in post-autologous transplant patients support increased differentiation of cytotoxic CD8 effector cells, contributing to persistent immune activation in aging and after transplant (Lee-Chang et al, Blood, 2014). Chronic graft vs host disease (CGVHD), the principle cause of non-relapse morbidity and mortality after allogeneic transplantation, is a major focus for research in the PDCMF core. We have supported the efforts of the multidisciplinary CGVHD clinical team in an ongoing natural history protocol of CGVHD (P.I. Steven Pavletic: 04-C-0281) by characterizing immunologic changes of CGVHD. Furthermore, we have supported four therapeutic trials for CGVHD patient populations: (1) We have assessed expression of leukotriene receptors (LTR) in leukocytes and CRTH2 receptors on T cells and in blood and bronchial lavage fluids to define the role of Th2 lineage T cells and leukotriences in progressive fibrosis of lung airways in patients developing bronchiolitis obliterans, a severe complication of CGVHD (08-C-0097: P. I. Ronald Gress and Kirsten Williams). (2) We have assessed the effect of Imatinib, aTGFbeta signaling inhibitor, on Th17 and Treg populations, as part of a collaborative trial testing Imatinib therapy on sclerotic cutantaneous CGVHD (Dermatology and Pediatric Branch, protocol 08-C-0148, P.I. Edward Cowen and Kristin Baird)(Baird et al, Biol Blood Marrow Transpl, 2015). (3) We are analyzing changes in inflammatory gene expression in a trial of Pomalidomide (12-C-0197; P.I. Steven Pavletic) to assess efficacy against fibrosis in CGVHD patients. (4) Finally we have supported a trial of topical therapy for severe oral CGVHD (12-C-0068; P.I. Steven Pavletic/Jacqueline Mays). This extensive experience in immunologic characterization of CGVHD has also supported our participation in the CGVHD consensus report on CGVHD biomarker studies (Paczesny et al, Biol Blood Marrow Transpl, 2015). As part of our studies of the pathogenesis of CGVHD, we have characterized regulatory T cells in CGVHD through coordinated studies of blood and tissue. These studies determined that FoxP3+ regulatory T cells (Treg) increased in proportion to T effectors in tissue infiltrates in oral and cutaneous lichenoid cGVHD. Both T effector and FoxP3+ Treg cells expressed Tbet and the chemokine receptor CXCR3, consistent with a common mechanism of chemokine-mediated migration into tissue. These studies also demonstrated the presence of Treg expressing Furthermore, functional markers (ICOS and CD39) in both blood and in cGVHD target tissues. The 'activated' CD45RA-FoxP3hi subset of Treg cells, which highly expresses functional markers, was found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg functional capacity in cGVHD, and support efforts to expand Treg cells in vivo as therapy. (Imanguli et al, Leukemia 2014) In studies of CGVHD pathogenesis, we profiled gene expression of circulating monocytes in CGVHD patients, to use these cells as in situ reporter cells for systemic cytokine patterns in order to test the hypothesis that Interferon (IFN)-induced inflammatory processes may underlie many of the systemic processes in CGVHD (Imanguli et al, 2009; Hakim, 2010). Based on microarray analysis and confirmed by multiplex RNA assessments (supported by an NCI Staff Scientist Career Development Award), we determined that pathways induced by IFN were consistently upregulated across a broad spectrum of CGVHD patients, both those with severe inflammatory infiltrates in tissue and those with widespread sclerotic involvement. IFN-inducible genes, including ones specifically induced by type I IFN, were upregulated in parallel at the time of onset of CGVHD, and were reduced during treatment and after resolution of CGVHD symptoms. In addition, we found a consistent upregulation of receptor genes from the innate immune TLR/NLR/CLR pathways; these pathways are triggered by debris from dead cells to stimulate phagocytosis, induce IFNa production, and form inflammasomes. Many of these receptors are also inducible by IFN, consistent with a self-reinforcing inflammatory process sustaining CGVHD. These interlocking assessments, performed on a broad spectrum of patients severely affected with CGVHD, support a new model for the initiation and persistence of CGVHD. This model defines CGVHD as a disorder of inflammation-driven immune dysregulation and these results support a new range of options for therapy of CGVHD through interdiction of interferon pathways.
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