Immune reconstitution following autologous and allogeneic stem cell transplant View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2009-2017

FUNDING AMOUNT

6677577 USD

ABSTRACT

SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols developed within ETIB. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from all ongoing ETIB protocols are processed and preserved by the PDCMF. 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. The work of this core is supported by close collaborative relationships with the Cell Processing Service of DTM, for support of microarray analysis; the ETIB Flow Cytometry Facility, for support of sorting of clinical products; the ETIB T Cell Facility and the laboratory of Ronald Gress, for technical support in RNA and DNA isolation and quantitative assays. PDCMF supports studies of lymphocyte reconstitution following ETIB transplant trials that include: (1) non-myeloablative reduced intensity allogeneic transplant for lymphoma using sibling and matched-unrelated donors, (2) autologous transplantation for myeloma and for systemic autoimmunity, and (3) myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136, 15-C-0067; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). We also support 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, 13-C-0132; PI: Dennis Hickstein) and primary immune deficiencies (16-C-0003, PI: Jennifer Kanakry (all ETIB)) by monitoring repopulation of deficient lineages after allogeneic transplant and by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism. Finally, in collaborations, we have analyzed allogeneic transplants of sickle cell disease (03-H-0170; PIs John Tisdale and Matthew Hsieh) and have examined immune reconstitution after radiation/chemotherapy treatment of glioblastoma (Johns Hopkins J1389; PIs Jian Campian and Stuart Grossman); the latter study is currently in press (Campian, J Neurol Oncol). We have focused on immune reconstitution in a matched unrelated donor allogeneic transplant trial (07-C-0195: PI Steven Pavletic) comparing two regimens of GVHD prophylaxis, one utilizing antibody-mediated depletion of host/donor lymphocytes at transplant, the second using immune suppressive agents. We determined that the lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers, as compared to that in patients with immune suppression alone. The lymphocyte repopulation differences between the two arms correlated with significant increases in early viral infections and relapse in the lymphocyte-depleted arm, and with significant increases in chronic GVHD (CGVHD) in the immune suppressive arm. Most of the patients developing CGVHD had an expanded population of CD8+ T memory stem cells (Tscm) (CD45RA+CCR7dimCD95+). In both anti-tumor studies and in autoimmunity, this subpopulation is known to be associated with persistent expansion of CD8 effectors. In contrast, we identified a 10 fold increase (favoring the lymphodepletion arm) in the median ratio of Treg cells to either naive CD4 or naive CD8 cells at 6 months, a time prior to onset of CGVHD. In collaborative studies of sickle cell disease transplants (03-C-0170), treated under a regimen that prevented both acute and chronic GVHD, we had similarly determined that Treg expanded at 1 - 3 months post transplant. These findings are consistent with evidence of a key role for the level of Treg cells in controlling CGVHD and the possibility that Tscm may contribute to CGVHD. These studies of relative levels of Tscm and Treg cells are being extended to examine the early weeks after transplant in 07-C-0195, and in prospective studies of immune reconstitution in all current allogeneic transplant protocols in the branch. CGVHD is the principal non-relapse cause of morbidity and mortality after allogeneic transplantation, and has been 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. We have proposed that Interferon (IFN)-induced factors recruit Th1/Tc1 effector T and regulatory cells into CGVHD targeted tissues (Imanguli et al, Blood 2009; Imanguli et al Leukemia 2014). We have profiled gene expression of circulating monocytes in CGVHD patients, to use these cells as in situ reporter cells for systemic cytokine patterns (Hakim et al, J Immunol 2016). Based on microarray analysis and confirmed by multiplex RNA assessments, we determined that gene expression 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. In serial analyses of individual CGVHD patients, we determined that IFN-inducible genes, including ones specifically induced by type I IFN, were upregulated in parallel at onset of CGVHD, and were reduced during treatment and after resolution of CGVHD symptoms. Furthermore, we found a consistent upregulation of receptor genes from the innate immune system (IIS) which respond to cellular damage by inducing Type I IFN production. We therefore proposed a self-reinforcing inflammatory process sustaining CGVHD, wherein cellular damage triggered IIS activation and IFN production, which in turn stimulated differentiation and recruitment to tissue of Th1/Tc1 and Th17 effectors, continuing a cycle of damage. Based on these analyses we have established flow cytometry panels to assess Th1/Tc1 effector and Treg cell levels in blood, ELISA panels to assess IFN inducible chemokines, and custom probe sets to assess the gene expression profiles we have identified. These are in use in current CGVHD therapeutic trials. This extensive experience in immunologic characterization of CGVHD has also supported our participation in the CGVHD consensus report on CGVHD biology and in a review of new immunomodulatory therapies in CGVHD (Cooke, Biol Blood Marrow Transpl, 2017; Im, Leukemia, 2017). Finally, we have supported therapeutic trials for CGVHD patient populations by supporting biospecimen preservation (both blood and tissues) and by CGVHD assays. (1) We track Treg and Tscm immune reconstitution in a new allogeneic transplantation trial using Keratinocyte Growth Factor (Pallifermin) to reduce the incidence of GVHD (15-C-0067: PI Steven Pavletic/Lauren Curtis). (2) We analyzed T and B cells of a trial of Pomalidomide (12-C-0197; PIS Lauren Curtis/Steven Pavletic), which produced a partial response in CGVHD symptoms in 2/3 of evaluable patients. Pomalidomide treatment was associated with significant increases in circulating IL-2 and in levels of Treg cells; this is consistent with a role for Pomalidomide in Treg modulation in CGVHD. (3) We provide pharmacodynamics and BAL and sputum preservation for newly initiated trials of an oral neutrophil elastase inhibitor, used to reduce neutrophil activation in Bronchiolitis Obliterans (16-C-0060: PI Steven Pavletic/Annie Im). (4) We assay cytokine induced STAT phosphorylation in studies of Baracitinib, an inhibitor of JAK1/JAK2 mediated immune activation (PI Steven Pavletic/Annie Im). In all these trials, we are assessing the effects of these therapies on the T cell, ELISA and gene expression biomarkers that we have developed. More... »

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The work of this core is supported by close collaborative relationships with the Cell Processing Service of DTM, for support of microarray analysis; the ETIB Flow Cytometry Facility, for support of sorting of clinical products; the ETIB T Cell Facility and the laboratory of Ronald Gress, for technical support in RNA and DNA isolation and quantitative assays. PDCMF supports studies of lymphocyte reconstitution following ETIB transplant trials that include: (1) non-myeloablative reduced intensity allogeneic transplant for lymphoma using sibling and matched-unrelated donors, (2) autologous transplantation for myeloma and for systemic autoimmunity, and (3) myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136, 15-C-0067; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). We also support 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, 13-C-0132; PI: Dennis Hickstein) and primary immune deficiencies (16-C-0003, PI: Jennifer Kanakry (all ETIB)) by monitoring repopulation of deficient lineages after allogeneic transplant and by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism. Finally, in collaborations, we have analyzed allogeneic transplants of sickle cell disease (03-H-0170; PIs John Tisdale and Matthew Hsieh) and have examined immune reconstitution after radiation/chemotherapy treatment of glioblastoma (Johns Hopkins J1389; PIs Jian Campian and Stuart Grossman); the latter study is currently in press (Campian, J Neurol Oncol). We have focused on immune reconstitution in a matched unrelated donor allogeneic transplant trial (07-C-0195: PI Steven Pavletic) comparing two regimens of GVHD prophylaxis, one utilizing antibody-mediated depletion of host/donor lymphocytes at transplant, the second using immune suppressive agents. We determined that the lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers, as compared to that in patients with immune suppression alone. The lymphocyte repopulation differences between the two arms correlated with significant increases in early viral infections and relapse in the lymphocyte-depleted arm, and with significant increases in chronic GVHD (CGVHD) in the immune suppressive arm. Most of the patients developing CGVHD had an expanded population of CD8+ T memory stem cells (Tscm) (CD45RA+CCR7dimCD95+). In both anti-tumor studies and in autoimmunity, this subpopulation is known to be associated with persistent expansion of CD8 effectors. In contrast, we identified a 10 fold increase (favoring the lymphodepletion arm) in the median ratio of Treg cells to either naive CD4 or naive CD8 cells at 6 months, a time prior to onset of CGVHD. In collaborative studies of sickle cell disease transplants (03-C-0170), treated under a regimen that prevented both acute and chronic GVHD, we had similarly determined that Treg expanded at 1 - 3 months post transplant. These findings are consistent with evidence of a key role for the level of Treg cells in controlling CGVHD and the possibility that Tscm may contribute to CGVHD. These studies of relative levels of Tscm and Treg cells are being extended to examine the early weeks after transplant in 07-C-0195, and in prospective studies of immune reconstitution in all current allogeneic transplant protocols in the branch. CGVHD is the principal non-relapse cause of morbidity and mortality after allogeneic transplantation, and has been 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. We have proposed that Interferon (IFN)-induced factors recruit Th1/Tc1 effector T and regulatory cells into CGVHD targeted tissues (Imanguli et al, Blood 2009; Imanguli et al Leukemia 2014). We have profiled gene expression of circulating monocytes in CGVHD patients, to use these cells as in situ reporter cells for systemic cytokine patterns (Hakim et al, J Immunol 2016). Based on microarray analysis and confirmed by multiplex RNA assessments, we determined that gene expression 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. In serial analyses of individual CGVHD patients, we determined that IFN-inducible genes, including ones specifically induced by type I IFN, were upregulated in parallel at onset of CGVHD, and were reduced during treatment and after resolution of CGVHD symptoms. Furthermore, we found a consistent upregulation of receptor genes from the innate immune system (IIS) which respond to cellular damage by inducing Type I IFN production. We therefore proposed a self-reinforcing inflammatory process sustaining CGVHD, wherein cellular damage triggered IIS activation and IFN production, which in turn stimulated differentiation and recruitment to tissue of Th1/Tc1 and Th17 effectors, continuing a cycle of damage. Based on these analyses we have established flow cytometry panels to assess Th1/Tc1 effector and Treg cell levels in blood, ELISA panels to assess IFN inducible chemokines, and custom probe sets to assess the gene expression profiles we have identified. These are in use in current CGVHD therapeutic trials. This extensive experience in immunologic characterization of CGVHD has also supported our participation in the CGVHD consensus report on CGVHD biology and in a review of new immunomodulatory therapies in CGVHD (Cooke, Biol Blood Marrow Transpl, 2017; Im, Leukemia, 2017). Finally, we have supported therapeutic trials for CGVHD patient populations by supporting biospecimen preservation (both blood and tissues) and by CGVHD assays. (1) We track Treg and Tscm immune reconstitution in a new allogeneic transplantation trial using Keratinocyte Growth Factor (Pallifermin) to reduce the incidence of GVHD (15-C-0067: PI Steven Pavletic/Lauren Curtis). (2) We analyzed T and B cells of a trial of Pomalidomide (12-C-0197; PIS Lauren Curtis/Steven Pavletic), which produced a partial response in CGVHD symptoms in 2/3 of evaluable patients. 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2 schema:amount N959a521340f84e6eb8b639326f99e732
3 schema:description SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols developed within ETIB. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from all ongoing ETIB protocols are processed and preserved by the PDCMF. 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. The work of this core is supported by close collaborative relationships with the Cell Processing Service of DTM, for support of microarray analysis; the ETIB Flow Cytometry Facility, for support of sorting of clinical products; the ETIB T Cell Facility and the laboratory of Ronald Gress, for technical support in RNA and DNA isolation and quantitative assays. PDCMF supports studies of lymphocyte reconstitution following ETIB transplant trials that include: (1) non-myeloablative reduced intensity allogeneic transplant for lymphoma using sibling and matched-unrelated donors, (2) autologous transplantation for myeloma and for systemic autoimmunity, and (3) myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136, 15-C-0067; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). We also support 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, 13-C-0132; PI: Dennis Hickstein) and primary immune deficiencies (16-C-0003, PI: Jennifer Kanakry (all ETIB)) by monitoring repopulation of deficient lineages after allogeneic transplant and by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism. Finally, in collaborations, we have analyzed allogeneic transplants of sickle cell disease (03-H-0170; PIs John Tisdale and Matthew Hsieh) and have examined immune reconstitution after radiation/chemotherapy treatment of glioblastoma (Johns Hopkins J1389; PIs Jian Campian and Stuart Grossman); the latter study is currently in press (Campian, J Neurol Oncol). We have focused on immune reconstitution in a matched unrelated donor allogeneic transplant trial (07-C-0195: PI Steven Pavletic) comparing two regimens of GVHD prophylaxis, one utilizing antibody-mediated depletion of host/donor lymphocytes at transplant, the second using immune suppressive agents. We determined that the lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers, as compared to that in patients with immune suppression alone. The lymphocyte repopulation differences between the two arms correlated with significant increases in early viral infections and relapse in the lymphocyte-depleted arm, and with significant increases in chronic GVHD (CGVHD) in the immune suppressive arm. Most of the patients developing CGVHD had an expanded population of CD8+ T memory stem cells (Tscm) (CD45RA+CCR7dimCD95+). In both anti-tumor studies and in autoimmunity, this subpopulation is known to be associated with persistent expansion of CD8 effectors. In contrast, we identified a 10 fold increase (favoring the lymphodepletion arm) in the median ratio of Treg cells to either naive CD4 or naive CD8 cells at 6 months, a time prior to onset of CGVHD. In collaborative studies of sickle cell disease transplants (03-C-0170), treated under a regimen that prevented both acute and chronic GVHD, we had similarly determined that Treg expanded at 1 - 3 months post transplant. These findings are consistent with evidence of a key role for the level of Treg cells in controlling CGVHD and the possibility that Tscm may contribute to CGVHD. These studies of relative levels of Tscm and Treg cells are being extended to examine the early weeks after transplant in 07-C-0195, and in prospective studies of immune reconstitution in all current allogeneic transplant protocols in the branch. CGVHD is the principal non-relapse cause of morbidity and mortality after allogeneic transplantation, and has been 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. We have proposed that Interferon (IFN)-induced factors recruit Th1/Tc1 effector T and regulatory cells into CGVHD targeted tissues (Imanguli et al, Blood 2009; Imanguli et al Leukemia 2014). We have profiled gene expression of circulating monocytes in CGVHD patients, to use these cells as in situ reporter cells for systemic cytokine patterns (Hakim et al, J Immunol 2016). Based on microarray analysis and confirmed by multiplex RNA assessments, we determined that gene expression 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. In serial analyses of individual CGVHD patients, we determined that IFN-inducible genes, including ones specifically induced by type I IFN, were upregulated in parallel at onset of CGVHD, and were reduced during treatment and after resolution of CGVHD symptoms. Furthermore, we found a consistent upregulation of receptor genes from the innate immune system (IIS) which respond to cellular damage by inducing Type I IFN production. We therefore proposed a self-reinforcing inflammatory process sustaining CGVHD, wherein cellular damage triggered IIS activation and IFN production, which in turn stimulated differentiation and recruitment to tissue of Th1/Tc1 and Th17 effectors, continuing a cycle of damage. Based on these analyses we have established flow cytometry panels to assess Th1/Tc1 effector and Treg cell levels in blood, ELISA panels to assess IFN inducible chemokines, and custom probe sets to assess the gene expression profiles we have identified. These are in use in current CGVHD therapeutic trials. This extensive experience in immunologic characterization of CGVHD has also supported our participation in the CGVHD consensus report on CGVHD biology and in a review of new immunomodulatory therapies in CGVHD (Cooke, Biol Blood Marrow Transpl, 2017; Im, Leukemia, 2017). Finally, we have supported therapeutic trials for CGVHD patient populations by supporting biospecimen preservation (both blood and tissues) and by CGVHD assays. (1) We track Treg and Tscm immune reconstitution in a new allogeneic transplantation trial using Keratinocyte Growth Factor (Pallifermin) to reduce the incidence of GVHD (15-C-0067: PI Steven Pavletic/Lauren Curtis). (2) We analyzed T and B cells of a trial of Pomalidomide (12-C-0197; PIS Lauren Curtis/Steven Pavletic), which produced a partial response in CGVHD symptoms in 2/3 of evaluable patients. Pomalidomide treatment was associated with significant increases in circulating IL-2 and in levels of Treg cells; this is consistent with a role for Pomalidomide in Treg modulation in CGVHD. (3) We provide pharmacodynamics and BAL and sputum preservation for newly initiated trials of an oral neutrophil elastase inhibitor, used to reduce neutrophil activation in Bronchiolitis Obliterans (16-C-0060: PI Steven Pavletic/Annie Im). (4) We assay cytokine induced STAT phosphorylation in studies of Baracitinib, an inhibitor of JAK1/JAK2 mediated immune activation (PI Steven Pavletic/Annie Im). In all these trials, we are assessing the effects of these therapies on the T cell, ELISA and gene expression biomarkers that we have developed.
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