title: Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells.
abstract: BACKGROUND
  Heat shock proteins (Hsps) are stress induced proteins with immunomodulatory properties. The Hsp70 of Mycobacterium tuberculosis (TBHsp70) has been shown to have an anti-inflammatory role on rodent autoimmune arthritis models, and the protective effects were demonstrated to be dependent on interleukin-10 (IL-10). We have previously observed that TBHsp70 inhibited maturation of dendritic cells (DCs) and induced IL-10 production by these cells, as well as in synovial fluid cells.
  
  
  RESULTS
  We investigated if TBHsp70 could inhibit allograft rejection in two murine allograft systems, a transplanted allogeneic melanoma and a regular skin allograft. In both systems, treatment with TBHsp70 significantly inhibited rejection of the graft, and correlated with regulatory T cells (Tregs) recruitment. This effect was not tumor mediated because injection of TBHsp70 in tumor-free mice induced an increase of Tregs in the draining lymph nodes as well as inhibition of proliferation of lymph node T cells and an increase in IL-10 production. Finally, TBHsp70 inhibited skin allograft acute rejection, and depletion of Tregs using a monoclonal antibody completely abolished this effect.
  
  
  CONCLUSIONS
  We present the first evidence for an immunosuppressive role for this protein in a graft rejection system, using an innovative approach--immersion of the graft tissue in TBHsp70 solution instead of protein injection. Also, this is the first study that demonstrates dependence on Treg cells for the immunosuppressive role of TBHsp70. This finding is relevant for the elucidation of the immunomodulatory mechanism of TBHsp70. We propose that this protein can be used not only for chronic inflammatory diseases, but is also useful for organ transplantation management.
authors.affiliation: Faculdade de Biociências e Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Thiago J
authors.initials: TJ
authors.lastname: Borges
authors.forename: Bárbara N
authors.initials: BN
authors.lastname: Porto
authors.forename: César A
authors.initials: CA
authors.lastname: Teixeira
authors.forename: Marcelle
authors.initials: M
authors.lastname: Rodrigues
authors.forename: Felipe D
authors.initials: FD
authors.lastname: Machado
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Ornaghi
authors.forename: Ana Paula D
authors.initials: AP
authors.lastname: de Souza
authors.forename: Fabio
authors.initials: F
authors.lastname: Maito
authors.forename: Wander R
authors.initials: WR
authors.lastname: Pavanelli
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Cristina
authors.initials: C
authors.lastname: Bonorino
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002908:Chronic Disease; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013582:Synovial Fluid / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014184:Transplantation, Homologous
chemical_list: D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10