Avaliação da reconstituição imunológica em pacientes com diabete ...

ABSTRACTFarias, K.C.R.M. Analysis of immune reconstitution in type 1 diabetes and multiple sclerosispatients following hematopoeitic stem cell transplantation. 2006. 286p. Thesis (Doctoral) –Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 2006.Clinical trials have indicated that autologous hematopoietic stem cell transplantation (AHSCT) canpersistently suppress inflammatory disease activity in a subset of patients with autoimmune diseases(AIDs), but the mechanism of action of the AHSCT has not yet been totally elucidated. The rationalefor HSCT in autoimmune diseases has been the notion that intensive immune depletion couldeliminate autoreactive immune cells irrespective of antigenic specificity and that regenerating theimmune system from hematopoietic precursors could reestablish tolerance. The goal of this work wasto evaluate the immune reconstitution in patients with type 1 diabetes mellitus (DM1; N=11) andmultiple sclerosis (MS; N=18) who received AHSCT. The immune reconstitution observed in the DM1patients (one year follow-up) and in the MS patients (two years follow-up) was characterized byperipheral thymic-independent mechanisms. After transplantation, there was a predominance ofcentral-memory T cells, effector-memory T cells and differentiated-effector T cells, mainly of the CD8 +T cell subset. These cells probably originate from peripheral homeostatic proliferation of residualmemory T cells that have survived the conditioning chemotherapy or were reinfused with the HSCgraft. The numbers of naive CD4 + and CD8 + T cells, including the recent-thymic emigrantsCD4 + CD45RA + CD31 + , did not revert to baseline levels during follow-up. After transplant, there was apredominance of T H 1 cells, mainly CD8 + T cells, producing INF-γ e TNF-α. In contrast, it was observedan increased percentage of CD4 + and CD8 + T cells producing T H 2 cytokines (IL4, IL-5 and IL-10) atpre-conditioning and at some time points after AHSCT. Analysis of the T cell receptor Vβ repertoire byTCRBV CDR3 spectratyping identified four basic patterns of repertoire reconstitution. The pattern thatconsisted of reconstitution of diversity from a normally diverse repertoire was the most dominant in theanalyzed patients. For some Vβ families were observed a pattern that consisted of recovery ofdiversity from a restricted repertoire, suggesting increased repertoire diversity after AHSCT. Therewere changes in the composition of the T cell repertoire post-AHSCT, evidenced by qualitative andquantitative alterations in the CDR3 peaks, which might explain the induction of the remission of the