title: HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen.
abstract: In allogeneic hematopoietic cell transplantation (HCT), donor T cell-mediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8(+) T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow (BM) cells required for induction of chimerism. Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are known to induce apoptosis of cancer cells and reduce production of proinflammatory cytokines by nonmalignant cells. Here, we report that SAHA inhibits the proliferative and cytotoxic activity of anti-CD3-activated T cells. Administration of low-dose SAHA reduces cytokine production and ameliorates the cytokine storm syndrome triggered by anti-CD3. Conditioning with anti-CD3 and SAHA allows induction of chimerism with lower doses of donor BM cells in old nonautoimmune and autoimmune lupus mice. In addition, conditioning with anti-CD3 and SAHA allows donor CD8(+) T cell-mediated GVA activity to reverse lupus glomerulonephritis without causing GVHD. These results indicate that conditioning with anti-CD3 and HDAC inhibitors represent a radiation-free and GVHD-preventative regimen with clinical application potential.
authors.affiliation: Department of Diabetes and Endocrinology, Division of Hematology and Hematopoietic Cell Transplantation, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010-0269, USA.
authors.forename: Nainong
authors.initials: N
authors.lastname: Li
authors.forename: Dongchang
authors.initials: D
authors.lastname: Zhao
authors.forename: Mark
authors.initials: M
authors.lastname: Kirschbaum
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Chia-Lei
authors.initials: CL
authors.lastname: Lin
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D046528:Chimerism / Q000139:chemically induced / Q000187:drug effects*; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D019172:Transplantation Conditioning; D000077337:Vorinostat
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat