Abstract
BackgroundHeat 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.Methodology/Principal FindingsWe 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/SignificanceWe 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.
Highlights
Heat shock proteins (Hsp) are highly immunogenic proteins, though conserved between mammals and microorganisms
No differences were observed for the other cytokines analyzed, including TGF-b. These results indicated that tuberculosis Hsp70 (TBHsp70) treatment leads to suppression of lymph node T cell proliferation in vitro, and this is associated with the upregulation of IL-10 production and inhibition of TNF-a
We investigated the ability of TBHsp70 to inhibit allograft rejection in two different models as well as the mechanism mediating this effect
Summary
Heat shock proteins (Hsp) are highly immunogenic proteins, though conserved between mammals and microorganisms. Because the total number of cells was increased twofold in the lymph nodes of tumor-treated animals, the total increase in CD4+ CD25+ Foxp3+ was approximately four-fold, compared to the PBS-injected animals (Fig. 3A) This result supported our hypothesis that TBHsp could induce Treg cells in the draining lymph node. No differences were observed for the other cytokines analyzed, including TGF-b These results indicated that TBHsp treatment leads to suppression of lymph node T cell proliferation in vitro, and this is associated with the upregulation of IL-10 production and inhibition of TNF-a. Mice receiving TBHsp70-treated skin graft presented prolonged acceptance of graft until day 17 (Fig. 4B) These results suggested that treatment with TBHsp significantly delays skin allograft rejection (p = 0.0455). TBHsp70-induced delay of skin graft rejection is mediated by Treg cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
