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.

C/EBPβ and C/EBPδ transcription factors are inhibited by Hsp70 treatment, and their inhibition occurs via the TLR2-ERK-STAT3-IL-10 pathway in BMDCs, mediating the anti-inflammatory effects of Hsp70.

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.

ResumoO objetivo deste trabalho foi avaliar o efeito dos espaçamentos de plantio em linhas simples e duplas na área basal, volume de madeira com casca por hectare, densidade básica do tronco e biomassa arbórea de Eucalyptus grandis Hill ex Maiden (clone G-21) manejado no sistema de curta rotação. O ensaio foi composto por quatro espaçamentos de plantio: 3,0 m × 1,0 m × 2,0 m (linha dupla), 3,0 m × 1,0 m (linha simples), 3,0 m × 1,0 m × 1,0 m (linha dupla) e 3,0 m × 0,5 m (linha simples), sendo avaliado aos 12 meses e 24 meses após o plantio. As principais diferenças significativas foram encontradas no segundo período de avaliação para os fatores de variação considerados -espaçamento e idade. A área basal aumentou com o adensamento das florestas, embora o volume não tenha seguido a mesma tendência aos 24 meses de plantio. A densidade básica aumentou com a idade apenas nos espaçamentos simples. No estudo da alocação de biomassa nos diferentes compartimentos da árvore, verificou-se uma maior proporção de biomassa de tronco com a idade, bem como nos espaçamentos mais adensados. Uma das maiores produções florestais (65 Mg ha -1 ) foi encontrada no espaçamento 3,0 m × 1,0 m aos 24 meses de idade. AbstractThe objective of this work was to analyze the effect of single and double planting spacing on the basal area, stem wood and bark volume per hectare, stem basic density and above-ground biomass of Eucalyptus grandis Hill ex Maiden (G-21 clone) managed under the short rotation coppice system. Four planting spacings were considered: 3.0 m × 1.0 m × 2.0 m (double row), 3.0 m × 1.0 m (single row), 3.0 m × 1.0 m × 1.0 m (double row) and 3.0 m × 0.5 m (single row), which were evaluated at 12 months and at 24 months after planting. Main significant differences were found at 12 months after planting for both factors spacing and age. Basal area increased as planting densification, although the volume did not show the same trend at 24 months after planting. Basic density increased as age only at single rows. In the study of the biomass allocation in the different tree compartments, it was verified a higher proportion of stem biomass on older treatments and denser spacings. One of the highest forest productions (65 Mg ha -1 ) was found in the 3 m × 1 m planting spacing at 24 months of age.

We have found that the patterns of innate and adaptive immune responses at 3 years of age were not affected by the fact of the children having being born preterm or at term.