Disease severity and mortality can be independently regulated in a mouse model of experimental graft versus host disease.

Graft versus host disease (GVHD) is the major limitation of allogeneic hematopoietic stem cell transplantation (HSCT) presenting high mortality and morbidity rates. However, the exact cause of death is not completely understood and does not correlate with specific clinical and histological parameters of disease. Here we show, by using a semi-allogeneic mouse model of GVHD, that mortality and morbidity can be experimentally separated. We injected bone marrow-derived dendritic cells (BMDC) from NOD2/CARD15-deficient donors into semi-allogeneic irradiated chimaeras and observed that recipients were protected from death. However, no protection was observed regarding clinical or pathological scores up to 20 days after transplantation. Protection from death was associated with decreased bacterial translocation, faster hematologic recovery and epithelial integrity maintenance despite mononuclear infiltration at day 20 post-GVHD induction with no skew towards different T helper phenotypes. The protected mice recovered from aGVHD and progressively reached scores compatible with healthy animals. Altogether, our data indicate that severity and mortality can be separate events providing a model to study transplant-related mortality.

Re-circulation of lymphocytes mediated by sphingosine-1-phosphate receptor-1 contributes to resistance against experimental infection with the protozoan parasite Trypanosoma cruzi.

T-cell mediated immune responses are critical for acquired immunity against infection by the intracellular protozoan parasite Trypanosoma cruzi. Despite its importance, it is currently unknown where protective T cells are primed and whether they need to re-circulate in order to exert their anti-parasitic effector functions. Here, we show that after subcutaneous challenge, CD11c(+)-dependent specific CD8(+) T-cell immune response to immunodominant parasite epitopes arises almost simultaneously in the draining lymph node (LN) and the spleen. However, until day 10 after infection, we observed a clear upregulation of activation markers only on the surface of CD11C(+)PDCA1(+) cells present in the LN and not in the spleen. Therefore, we hypothesized that CD8(+) T cells re-circulated rapidly from the LN to the spleen. We investigated this phenomenon by administering FTY720 to T. cruzi-infected mice to prevent egress of T cells from the LN by interfering specifically with signalling through sphingosine-1-phosphate receptor-1. In T. cruzi-infected mice receiving FTY720, CD8 T-cell immune responses were higher in the draining LN and significantly reduced in their spleen. Most importantly, FTY720 increased susceptibility to infection, as indicated by elevated parasitemia and accelerated mortality. Similarly, administration of FTY720 to mice genetically vaccinated with an immunodominant parasite antigen significantly reduced their protective immunity, as observed by the parasitemia and survival of vaccinated mice. We concluded that re-circulation of lymphocytes mediated by sphingosine-1-phosphate receptor-1 greatly contributes to acquired and vaccine-induced protective immunity against experimental infection with a human protozoan parasite.

Nod1 participates in the innate immune response to Pseudomonas aeruginosa.

The mammalian innate immune system recognizes pathogen-associated molecular patterns through pathogen recognition receptors. Nod1 has been described recently as a cytosolic receptor that detects specifically diaminopimelate-containing muropeptides from Gram-negative bacteria peptidoglycan. In the present study we investigated the potential role of Nod1 in the innate immune response against the opportunistic pathogen Pseudomonas aeruginosa. We demonstrate that Nod1 detects the P. aeruginosa peptidoglycan leading to NF-kappaB activation and that this activity is diminished in epithelial cells expressing a dominant-negative Nod1 construct or in mouse embryonic fibroblasts from Nod1 knock-out mice infected with P. aeruginosa. Finally, we demonstrate that the cytokine secretion kinetics and bacterial killing are altered in Nod1-deficient cells infected with P. aeruginosa in the early stages of infection.