Exploration of new mechanisms of epithelial barrier brekdown in acute gastrintestinal graft-versus-host-disease associated with alterations in "tight junctions"

• Grant number: 13/09319-0
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2013
• End date: May 31, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Erich Vinicius de Paula
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Acute graft-versus-host disease (aGVHD) is a major cause of premature death in hematopoietic stem cell transplantation (HSCT). From classic studies conducted in the 1980s, the breakdown of intestinal epithelial barrier in the initial phase of HSCT has been recognized as a critical pathophysiological event for aGVHD. This breakdown allows the translocation of antigens from the intestinal lumen and stimulates the activation of donor T lymphocytes, which act as effectors of the immune response that leads to diarrhea. The importance of these mechanisms is illustrated by a reduction in aGVHD in germ-free animals, and in patients receiving T-cell depleted grafs. In addition, a recent study pointed the intestine as the main target-organ of antigenic stimulation in the initial phases of aGVHD. However, the cellular mechanisms responsible for the breakdown of the intestinal epithelial barrier in the pre-clinical phase, and the effector mechanisms of diarrhea of aGVHD remain uncertain.The intestinal epithelium maintains its barrier function through junctional complexes, of which "tight junctions" (TJ) are considered the most important. Rather than static structures, TJ are dynamic multiprotein complexes that regulate the passage of solutes, upon the activation of signaling pathways and stimuli from the external environment. Over the past years, and protein interactions and environmental stimuli responsible for the regulation of the TJ function have been described in detail. Accordingly, these pathways have been evaluated in several diseases in which epithelial barrier breakdown is a potential pathogenic mechanism, so that TJ dysfunction were implicated in the pathophysiology of several immune-mediated diarrhea.Based on these informations, we plan to explore the role of structural and functional alterations of TJ in the pathophysiology of intestinal aGVHD, both in the pre-clinical and clinical phase. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES DA COSTA, LOREDANA NILKENES; COSTA-LIMA, CAROLINA; DE MEIRELLES, LUCIANA RODRIGUES; CARVALHO, RITA B.; COLELLA, MARCOS PAULO; PENTEADO ARANHA, FRANCISCO JOSE; VIGORITO, AFONSO CELSO; DE PAULA, ERICH VINICIUS. Association between histopathological alterations and diarrhea severity in acute intestinal graft-versus-host disease. MEDICINE, v. 97, n. 19, MAY 2018. (13/09319-0)

FERREIRA, F. L. B.; COLELLA, M. P.; MEDINA, S. S.; COSTA-LIMA, C.; FIUSA, M. M. L.; COSTA, L. N. G.; ORSI, F. A.; ANNICHINO-BIZZACCHI, J. M.; FERTRIN, K. Y.; GILBERTI, M. F. P.; et al. Evaluation of the immature platelet fraction contribute to the differential diagnosis of hereditary, immune and other acquired thrombocytopenias. SCIENTIFIC REPORTS, v. 7, JUN 13 2017. (13/09319-0)

FAIOTTO, VANESSA BOURY; FRANCI, DANIEL; ENZ HUBERT, RODOLFO MONTEIRO; DE SOUZA, GLEICE REGINA; LUZ FIUSA, MAIARA MARX; HOUNKPE, BIDOSSESSI WILFRIED; SANTOS, THIAGO MARTINS; CARVALHO-FILHO, MARCO ANTONIO; DE PAULA, ERICH VINICIUS. Circulating levels of the angiogenesis mediators endoglin, HB-EGF, BMP-9 and FGF-2 in patients with severe sepsis and septic shock. JOURNAL OF CRITICAL CARE, v. 42, p. 162-167, DEC 2017. (13/09319-0)

TANI, VANESSA M.; DA SILVA, THAMIRES BRANCO; ROGERIO, FABIO; DE PAULA, ERICH V.. Microvascular thrombosis in sepsis: An autopsy study. THROMBOSIS RESEARCH, v. 156, p. 23-25, AUG 2017. (13/09319-0)

COSTA-LIMA, CAROLINA; MARTINS MIRANDA, ELIANA CRISTINA; COLELLA, MARCOS PAULO; PENTEADO ARANHA, FRANCISCO JOSE; DE SOUZA, CARMINO ANTONIO; VIGORITO, AFONSO CELSO; DE PAULA, ERICH VINICIUS. Pretransplant beta(2)-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, v. 22, n. 7, p. 1329-1332, JUL 2016. (13/09319-0)

DE SOUZA, GLEICE REGINA; HOUNKPE, BIDOSSESSI WILFRIED; LUZ FIUSA, MAIARA MARX; COLELLA, MARINA PEREIRA; ANNICHINO-BIZZACCHI, JOYCE M.; TRAINA, FABIOLA; COSTA, FERNANDO FERREIRA; DE PAULA, ERICH VINICIUS. Tissue factor-dependent coagulation activation by heme: A thromboelastometry study. PLoS One, v. 12, n. 4, APR 24 2017. (15/24666-3, 14/00984-3, 13/09319-0)