Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease.
Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4(+) leukocytes in the inflammatory infiltrate on days +7 and +14 and of CD8(+) cells on day +7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that high-dose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD.
Godoi
D F
DF
Department of Internal Medicine, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. dannigodoi@usp.br
Cardoso
C R
CR
Ferraz
D B
DB
Provinciatto
P R
PR
Cunha
F Q
FQ
Silva
J S
JS
Voltarelli
J C
JC
D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D018928:Immunity, Mucosal / Q000187:drug effects; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012720:Severity of Illness Index; D016019:Survival Analysis; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D014302:Trinitrobenzenesulfonic Acid