Medicine and Health Sciences Commons^™

Variant Characterization Of A Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition Of Risk To Lynch Syndrome, Mouadh Barbirou, Amanda A. Miller, Amel Mezlini, Balkiss Bouhaouala-Zahar, Peter J. Tonellato

Department of Medical Oncology Faculty Papers

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, …

Mir-218-5p/Egfr Signaling In Arsenic-Induced Carcinogenesis, Ranakul Islam, Lei Zhao, Xiujuan Zhang, Ling-Zhi Liu

Department of Medical Oncology Faculty Papers

Background: Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear.

Methods: RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR …

Editorial: Hallmark Of Cancer: Reprogramming Of Cellular Metabolism, Baljinder Kaur, Yahya Sohrabi, Abhinav Achreja, Michael P. Lisanti, Ubaldo Emilio Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

No abstract provided.

Epigenetic Dysregulations In Arsenic-Induced Carcinogenesis, Ranakul Islam, Lei Zhao, Yifang Wang, Grace Lu-Yao, Ling-Zhi Liu

Department of Medical Oncology Faculty Papers

Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced …

A Telehealth-Delivered Tai Chi Intervention (Taichi4joint) For Managing Aromatase Inhibitor-Induced Arthralgia In Patients With Breast Cancer During Covid-19: Longitudinal Pilot Study, Sameh Gomaa, Carly West, Ana Maria Lopez, Tingting Zhan, Max Schnoll, Maysa Abu-Khalaf, Andrew B. Newberg, Kuang-Yi Wen

Department of Medical Oncology Faculty Papers

Background: Estrogen receptor-positive breast cancer is the most common type of breast cancer in postmenopausal women. Aromatase inhibitors (AIs) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop arthralgia, often resulting in poor adherence and decreased quality of life.

Objective: The study is a single-arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability, and potential efficacy of TaiChi4Joint, a remotely delivered 12-week tai chi intervention designed to relieve AI-induced joint pain.

Methods: Women diagnosed with stage 0-III breast cancer who received an AI for at least 2 …

Partial Treatment Response To Capmatinib In Met-Amplified Metastatic Intrahepatic Cholangiocarcinoma: Case Report & Review Of Literature, Daniel S Lefler, Marni Brisson Tierno, Babar Bashir

Department of Medical Oncology Faculty Papers

Cholangiocarcinoma is a highly morbid gastrointestinal malignancy for which available therapies are limited. Standard of care includes cytotoxic chemotherapies such as gemcitabine, platinum agents, nab-paclitaxel, and fluoropyrimidine analogues. However, tolerability of these regimens varies, and patients who do not tolerate chemotherapy have limited targeted therapies and immunotherapy options. In cholangiocarcinoma, mesenchymal-epithelial transition factor (MET) amplification may present an additional opportunity for a targeted therapeutic approach, especially considering emerging data in non-small cell lung cancer. In this case, we present a metastatic cholangiocarcinoma patient with high-level MET gene amplification for whom capmatinib, a tyrosine kinase inhibitor with activity against c-MET, …

The Role Of Hgf/Met Signaling In Metastatic Uveal Melanoma, Ryota Tanaka, Mizue Terai, Eric R Londin, Takami Sato

Department of Medical Oncology Faculty Papers

Hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signaling promotes tumorigenesis and tumor progression in various types of cancer, including uveal melanoma (UM). The roles of HGF/MET signaling have been studied in cell survival, proliferation, cell motility, and migration. Furthermore, HGF/MET signaling has emerged as a critical player not only in the tumor itself but also in the tumor microenvironment. Expression of MET is frequently observed in metastatic uveal melanoma and is associated with poor prognosis. It has been reported that HGF/MET signaling pathway activation is the major mechanism of treatment resistance in metastatic UM (MUM). To achieve maximal therapeutic benefit …

Phase 1 Study Of Safety, Tolerability And Immunogenicity Of The Human Telomerase (Htert)-Encoded Dna Plasmids Ino-1400 And Ino-1401 With Or Without Il-12 Dna Plasmid Ino-9012 In Adult Patients With Solid Tumors, Robert H Vonderheide, Kimberly A Kraynyak, Anthony F Shields, Autumn J Mcree, Jennifer Johnson, Weijing Sun, Ashish V Chintakuntlawar, Jan Pawlicki, Albert J Sylvester, Trevor Mcmullan, Robert Samuels, Joseph J Kim, David Weiner, Jean D Boyer, Matthew P Morrow, Laurent Humeau, Jeffrey M Skolnik

Department of Medical Oncology Faculty Papers

BACKGROUND: Human telomerase reverse transcriptase (hTERT) is frequently classified as a 'universal' tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.

METHODS: A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device …

Longitudinal Dynamics Of Circulating Tumor Cells And Circulating Tumor Dna For Treatment Monitoring In Metastatic Breast Cancer, Lorenzo Gerratana, Andrew A Davis, Qiang Zhang, Debora Basile, Giovanna Rossi, Kimberly Strickland, Alessandra Franzoni, Lorenzo Allegri, Zhaomei Mu, Youbin Zhang, Lisa E Flaum, Giuseppe Damante, William John Gradishar, Leonidas C Platanias, Amir Behdad, Hushan Yang, Fabio Puglisi, Massimo Cristofanilli

Department of Medical Oncology Faculty Papers

Liquid biopsy-based biomarkers, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). The aim of the study was to explore CTCs and ctDNA dynamics to better understand their potentially complementary role in describing MBC.

METHODS: The study retrospectively analyzed 107 patients with MBC characterized with paired CTCs and ctDNA assessments and a second prospective cohort, which enrolled 48 patients with MBC. CTCs were immunomagnetically isolated and ctDNA was quantified and then characterized through next-generation sequencing in the retrospective cohort and droplet digital polymerase chain reaction in the prospective …

Hypercalcemia Of Malignancy Attributed To Cosecretion Of Pth And Pthrp In Lung Adenocarcinoma, Jeffrey Kroopnick, Ubaldo E. Martinez-Outshoorn, Madalina Tuluc, Caroline S Kim

Department of Medical Oncology Faculty Papers

Introduction: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone.

Case report: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. …

Improving Nutrition And Immunity With Dry Chain And Integrated Pest Management Food Technologies In Lmics., Peetambar Dahal, Meghnath Dhimal, Krishna Belbase, Sundar Tiwari, John Groopman, Keith West, Bradley Pollock, Subodh Pyakurel, Ganga Acharya, Sunil Aryal, Yug Nath Ghimire, Manish Neupane, Rosina Poudel, Johan Van Ashbrouck, Keshavulu Kunusoth, Sarah De Saeger, Marthe De Boevre, Gokarna Gharti-Chhetri, Tek Bahadur Gurung, Kent J Bradford

Department of Medical Oncology Faculty Papers

No abstract provided.

Limited Immune Surveillance In Lymphoid Tissue By Cytolytic Cd4+ T Cells During Health And Hiv Disease., Marcus Buggert, Son Nguyen, Laura M. Mclane, Maria Steblyanko, Nadia Anikeeva, Dominic Paquin-Proulx, Perla M Del Rio Estrada, Yuria Ablanedo-Terrazas, Kajsa Noyan, Morgan A. Reuter, Korey Demers, Johan K. Sandberg, Michael A. Eller, Hendrik Streeck, Marianne Jansson, Piotr Nowak, Anders Sönnerborg, David H. Canaday, Ali Naji, E. John Wherry, Merlin L. Robb, Steven G Deeks, Gustavo Reyes-Teran, Yuri Sykulev, Annika C. Karlsson, Michael R. Betts

Department of Medical Oncology Faculty Papers

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and …

Tp53-Inducible Glycolysis And Apoptosis Regulator (Tigar) Metabolically Reprograms Carcinoma And Stromal Cells In Breast Cancer., Ying-Hui Ko, Marina Domingo-Vidal, Megan Roche, Zhao Lin, Diana Whitaker-Menezes, Erin Seifert, Claudia Capparelli, Madalina Tuluc, Ruth C. Birbe, Patrick Tassone, Joseph M. Curry, Àurea Navarro-Sabaté, Anna Manzano, Ramon Bartrons, Jaime Caro, Ubaldo E. Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates …

Applying Multiple Data Collection Tools To Quantify Human Papillomavirus Vaccine Communication On Twitter., Philip M. Massey, Amy Leader, Elad Yom-Tov, Alexandra Budenz, Kara Fisher, Ann C. Klassen

Department of Medical Oncology Faculty Papers

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. There are several vaccines that protect against strains of HPV most associated with cervical and other cancers. Thus, HPV vaccination has become an important component of adolescent preventive health care. As media evolves, more information about HPV vaccination is shifting to social media platforms such as Twitter. Health information consumed on social media may be especially influential for segments of society such as younger populations, as well as ethnic and racial minorities.

OBJECTIVE: The objectives of our study were to quantify HPV vaccine communication on …

Phase Ii Evaluation Of Dasatinib In The Treatment Of Recurrent Or Persistent Epithelial Ovarian Or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study., Russell J Schilder, William E Brady, Heather A Lankes, James V Fiorica, Mark S Shahin, Xun C Zhou, Robert S Mannel, Harsh B Pathak, Wei Hu, R Katherine Alpaugh, Anil K Sood, Andrew K Godwin

Department of Medical Oncology Faculty Papers

OBJECTIVES: Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC, and explored biomarkers for possible association with clinical outcome.

METHODS: Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100mg orally daily of dasatinib continuously until progression of disease …

Cell Membrane And Cytoplasmic Epidermal Growth Factor Receptor Expression In Pancreatic Ductal Adenocarcinoma., Amit Mahipal, Mary J Mcdonald, Agnieszka Witkiewicz, Brian I Carr

Department of Medical Oncology Faculty Papers

The significance of over-expression of epidermal growth factor receptor (EGFR) in pancreatic carcinoma is unclear. In this study, we examined the association between EGFR over-expression (membranous and cytoplasmic), the associated histopathologic features and clinical outcomes in post-resection pancreatic cancer patients. EGFR expression was determined immunohistochemically in 90 patients who underwent resection for pancreatic cancer. Cytoplasmic expression was considered positive if EGFR expression was seen in the cytoplasm in ≥ 10% of cells. Cell membrane staining was scored from 0 to 3+, with 2+ and 3+ being considered as membrane over-expression. Overall survival and progression-free survival were calculated using the Kaplan-Meier …

Phase I Evaluation Of Intravenous Ascorbic Acid In Combination With Gemcitabine And Erlotinib In Patients With Metastatic Pancreatic Cancer., Daniel A. Monti, Md, Edith Mitchell, Anthony J Bazzan, Susan Littman, George Zabrecky, Charles J Yeo, Madhaven V Pillai, Andrew B Newberg, Sandeep Deshmukh, Mark Levine

Department of Medical Oncology Faculty Papers

BACKGROUND: Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.

METHODS AND FINDINGS: 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of …

Complementary And Integrative Oncology In The Cross-Cultural Region Of The Middle East And South Asia., Eran Ben-Arye, Barrie Cassileth, Peter Heusser, Fatma Afifi, Bashar Saad, Senthamil R Selvan

Department of Medical Oncology Faculty Papers

No abstract provided.

A 2-Step Approach To Myeloablative Haploidentical Stem Cell Transplantation: A Phase 1/2 Trial Performed With Optimized T-Cell Dosing., Dolores Gross, Matthew Carabasi, Joanne Filicko-O'Hara, Margaret Kasner, John L Wagner, Beth Colombe, Patricia Cornett Farley, William O'Hara, Phyllis Flomenberg, Maria Werner-Wasik, Janet Brunner, Bijoyesh Mookerjee, Terry Hyslop, Mark Weiss, Neal Flomenberg

Department of Medical Oncology Faculty Papers

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg …

Ceacam1 Separates Graft-Versus-Host-Disease From Graft-Versus-Tumor Activity After Experimental Allogeneic Bone Marrow Transplantation., Sydney X Lu, Lucy W Kappel, Anne-Marie Charbonneau-Allard, Renée Atallah, Amanda M Holland, Claire Turbide, Vanessa M Hubbard, Jimmy A Rotolo, Marsinay Smith, David Suh, Christopher King, Uttam K Rao, Nury Yim, Johanne L Bautista, Robert R Jenq, Olaf Penack, Il-Kang Na, Chen Liu, George Murphy, Onder Alpdogan, Richard S Blumberg, Fernando Macian, Kathryn V Holmes, Nicole Beauchemin, Marcel R M Van Den Brink

Department of Medical Oncology Faculty Papers

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.

METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In …

Tumor-Derived Interleukin-10 As A Prognostic Factor In Stage Iii Patients Undergoing Adjuvant Treatment With An Autologous Melanoma Cell Vaccine., Amit Mahipal, Mizue Terai, David Berd, Inna Chervoneva, Kashyap Patel, Michael Mastrangelo, Takami Sato

Department of Medical Oncology Faculty Papers

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP).

METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind …

In Vitro Migration Of Cytotoxic T Lymphocyte Derived From A Colon Carcinoma Patient Is Dependent On Ccl2 And Ccr2., Klara Berencsi, Pyapalli Rani, Tianqian Zhang, Laura Gross, Michael Mastrangelo, Neal J Meropol, Dorothee Herlyn, Rajasekharan Somasundaram

Department of Medical Oncology Faculty Papers

BACKGROUND: Infiltration of colorectal carcinomas (CRC) with T-cells has been associated with good prognosis. There are some indications that chemokines could be involved in T-cell infiltration of tumors. Selective modulation of chemokine activity at the tumor site could attract immune cells resulting in tumor growth inhibition. In mouse tumor model systems, gene therapy with chemokines or administration of antibody (Ab)-chemokine fusion proteins have provided potent immune mediated tumor rejection which was mediated by infiltrating T cells at the tumor site. To develop such immunotherapeutic strategies for cancer patients, one must identify chemokines and their receptors involved in T-cell migration toward …

Epidermal Growth Factor Receptor Overexpression In Resected Pancreatic Cancer, Amit Mahipal, Mary J. Mcdonald, Agnieszka Witkiewicz, Brian I. Carr

Department of Medical Oncology Faculty Papers

Conclusions:

Membrane EGFR overexpression is associated with poorer clinical outcomes in patients with pancreatic cancer receiving adjuvant therapy post resection.

Cytoplasmic EGFR overexpression is not associated with clinical outcomes.

The Addition Of Rituximab To Fludarabine And Cyclophosphamide Improves Progression-Free Survival In Patients With Previously Treated Chronic Lymphocytic Leukemia., Amit Mahipal, Mark Weiss

Department of Medical Oncology Faculty Papers

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. There has been considerable progress in understanding the biology and treatment of CLL in last 20 years. The introduction of purine analogs (pentostatin, fludarabine, and cladribine) dramatically increased the response rates compared to alkylating agents. Combination chemoimmunotherapy has further improved the overall frequency of response to over 80% in treatment-naïve and over 60% in relapsed/ refractory disease, respectively.

In Vitro Methods For Generating Highly Purified Ebv Associated Tumor Antigen-Specific T Cells By Using Solid Phase T Cell Selection System For Immunotherapy, Jongming Li, Bijoyesh Mookerjee, John Wagner, Neal Flomenberg

Department of Medical Oncology Faculty Papers

Adoptive cell transfer immunotherapy has been utilized to treat EBV related human malignancies including post-transplant lymphoproliferative diseases, Hodgkin's lymphoma and nasopharyngeal carcinoma. However, there are limited options available for tumor antigen-specific T cell purification. Here we describe a novel solid phase T cell selection system, in which monocytes or EBV transformed B-lymphocytes are immobilized on solid support for antigen-specific T cell purification. We hypothesize and prove that antigen-specific T cells recognize their cognate antigens and bind to them faster than non-antigen specific T cells. Therefore antigen-specific T cells can be concentrated on the surface after removing the non-adherent cells by …

Ocular Surface Epithelia Contain Abcg2-Dependent Side Population Cells Exhibiting Features Associated With Stem Cells., Murat T Budak, Onder S Alpdogan, Mingyuan Zhou, Robert M Lavker, M A Murat Akinci, J Mario Wolosin

Department of Medical Oncology Faculty Papers

When cell populations are incubated with the DNA-binding dye Hoechst 33342 and subjected to flow cytometry analysis for Hoechst 33342 emissions, active efflux of the dye by the ABCG2/BCRP1 transporter causes certain cells to appear as a segregated cohort, known as a side population (SP). Stem cells from several tissues have been shown to possess the SP phenotype. As the lack of specific surface markers has hindered the isolation and subsequent biochemical characterization of epithelial stem cells this study sought to determine the existence of SP cells and expression of ABCG2 in the epithelia of the ocular surface and evaluate …

Gitr Activation Induces An Opposite Effect On Alloreactive Cd4(+) And Cd8(+) T Cells In Graft-Versus-Host Disease., Stephanie J Muriglan, Teresa Ramirez-Montagut, Onder Alpdogan, Thomas W Van Huystee, Jeffrey M Eng, Vanessa M Hubbard, Adam A Kochman, Kartono H Tjoe, Carlo Riccardi, Pier Paolo Pandolfi, Shimon Sakaguchi, Alan N Houghton, Marcel R M Van Den Brink

Department of Medical Oncology Faculty Papers

Glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) is a member of the tumor necrosis factor receptor (TNFR) family that is expressed at low levels on unstimulated T cells, B cells, and macrophages. Upon activation, CD4(+) and CD8(+) T cells up-regulate GITR expression, whereas immunoregulatory T cells constitutively express high levels of GITR. Here, we show that GITR may regulate alloreactive responses during graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Using a BMT model with major histocompatibility complex class I and class II disparity, we demonstrate that GITR stimulation in vitro and in vivo enhances alloreactive CD8(+)CD25(-) T …

Il-7 Enhances Peripheral T Cell Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation., Onder Alpdogan, Stephanie J Muriglan, Jeffrey M Eng, Lucy M Willis, Andrew S Greenberg, Barry J Kappel, Marcel R M Van Den Brink

Department of Medical Oncology Faculty Papers

We used clinically relevant murine allogeneic bone marrow transplantation (BMT) models to study the mechanisms by which IL-7 administration can improve posttransplant peripheral T cell reconstitution. After transplant we could distinguish two populations of mature donor T cells: (a) alloreactive T cells with decreased expression of CD127 (IL-7 receptor alpha chain) and (b) nonalloreactive T cells, which express CD127 and undergo homeostatic proliferation. IL-7 administration increased the homeostatic proliferation of nonalloreactive T cells, but had no effect on alloreactive T cells and the development of graft-versus-host disease. Allogeneic transplant of purified hematopoietic stem cells and adoptive transfer of thymocytes into …