Study of immunological mechanisms involved in the therapeutic response of patients with systemic sclerosis to autologous hematopoietic stem cells transplantation

• Grant number: 13/18678-3
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): November 01, 2013
• Effective date (End): August 18, 2017
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal researcher: Maria Carolina de Oliveira Rodrigues
• Grantee: Lucas Coelho Marlière Arruda
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
• Associated scholarship(s): 14/20922-2 - Evaluation of thymic function after autologous hematopoietic stem cell transplantation in systemic sclerosis patients, BE.EP.DR

Abstract

Systemic sclerosis (SSc) is a chronic connective tissue disease, characterized by microvascular lesions associated with different degrees of skin and internal organs fibrosis. It is classified in two main clinic forms, limited SSc and diffuse SSc. They differ in extent of cutaneous involvement, profile of serum autoantibodies, progression and distinct prognosis. The etiology of SSc remains unknown and the mechanisms involved in the pathogenesis are not completely understood, therefore the treatments available are limited. The pathogenesis of SSc involves abnormalities in the vascular and immune system, leading to vessels and vital organs fibrosis, characterized by three pathogenic processes: excessive deposition of collagen and other macromolecules of the connective tissue in the skin and internal organs (lungs, heart, gastrointestinal tract and kidneys); vascular lesions of small arteries, and changes in humoral and cellular immunity, as a result of autoimmune reactions. Currently, high-dose immunosuppression associated with autologous hematopoietic stem cell transplantation (HDI/AHSCT) are a promising alternative treatment for SSc progressive/severe, preventing disease progression and/or favoring the use of conventional treatment in refractory patients. The aim of the present study is to evaluate the immunological mechanisms involved in the therapeutic response of patients with SSc after the HDI/AHSCT, including the assessment of: i) immune reconstitution of T and B cells subsets; ii) suppression capacity of regulatory T cells; iii) serum autoantibodies, cytokines and chemokines; iv) expression of cytokines, chemokines and growth factors in pacients skin biopsies. The findings obtained in the present study could identify biomarkers of prognosis and/or therapeutic response involved in this type of treatment. Our hypothesis is that the HDI/AHSCT promotes a decrease in the numbers of memory T and B cells, a reducement in the autoantibody levels and cytokines/chemokines involved in the process of fibrosis and collagen deposition. Besides the treatment may increase the number and capacity of suppressive regulatory T cells, leading to regression of fibrotic skin area and clinical improvement. Thus, this study will help to clarify the immune mechanisms and the benefits of HDI/AHSCT in the treatment of SSc, which is necessary to improve the current clinical protocol. (AU)

Scientific publications

(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)

ARRUDA, LUCAS C. M.; LIMA-JUNIOR, JOAO R.; CLAVE, EMMANUEL; MORAES, DANIELA A.; DOUAY, CORINNE; FOURNIER, ISABELLE; MOINS-TEISSERENC, HELENE; COVAS, DIMAS T.; SIMOES, BELINDA P.; FARGE, DOMINIQUE; TOUBERT, ANTOINE; MALMEGRIM, KELEN C. R.; OLIVEIRA, MARIA CAROLINA. Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis. BONE MARROW TRANSPLANTATION, v. 53, n. 10, p. 1319-1327, OCT 2018. Web of Science Citations: 5.

ARRUDA, LUCAS C. M.; MALMEGRIM, KELEN C. R.; LIMA-JUNIOR, JOAO R.; CLAVE, EMMANUEL; DIAS, JULIANA B. E.; MORAES, DANIELA A.; DOUAY, CORINNE; FOURNIER, ISABELLE; MOINS-TEISSERENC, HELENE; ALBERDI, ANTONIO JOSE; COVAS, DIMAS T.; SIMOES, BELINDA P.; LANSIAUX, PAULINE; TOUBERT, ANTOINE; OLIVEIRA, MARIA CAROLINA. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. BLOOD ADVANCES, v. 2, n. 2, p. 126-141, JAN 23 2018. Web of Science Citations: 15.

ARRUDA, L. C. M.; CLAVE, E.; MOINS-TEISSERENC, H.; DOUAY, C.; FARGE, D.; TOUBERT, A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. CURRENT RESEARCH IN TRANSLATIONAL MEDICINE, v. 64, n. 2, p. 107-113, APR-JUN 2016. Web of Science Citations: 11.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ARRUDA, Lucas Coelho Marlière. Evaluation of immunological mechanisms associated with autologous hematopoietic stem cell transplantation in systemic sclerosis patients. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.