Peripheral effects induced in BALB/c mice infected with DENV by the intracerebral route.

The lack of an immunocompetent animal model for dengue mimicking the disease in humans is a limitation for advances in this field. Inoculation by intracerebral route of neuroadapted dengue strains in mice is normally lethal and provides a straightforward readout parameter for vaccine testing. However, systemic effects of infection and the immune response elicited in this model remain poorly described. In the present work, BALB/c mice infected by the intracerebral route with neuroadapted DENV2 exhibited several evidences of systemic involvement. DENV-inoculated mice presented virus infective particles in the brain followed by viremia, especially in late stages of infection. Infection induced cellular and humoral responses, with presence of activated T cells in spleen and blood, lymphocyte infiltration and tissue damages in brain and liver, and an increase in serum levels of some pro-inflammatory cytokines. Data highlighted an interplay between the central nervous system commitment and peripheral effects under this experimental condition.

Involvement of laminin and its receptor in abrogation of heart graft rejection by autoreactive T cells from Trypanosoma cruzi-infected mice.

Extracellular matrix ligands and receptors have been identified as determining in vivo lymphocyte positioning and activation, including effector functions in alloreactive responses. Herein we evaluated the involvement of laminin and its receptor, the very late antigen 6 (VLA-6) integrin, in CD4+ T cell-dependent autoreactivity, using a transplantation model for the autoimmune myocarditis occurring in mice chronically infected with Trypanosoma cruzi. Previous work showed that syngeneic mouse hearts grafted in the ears of chronic chagasic recipients were rejected through a CD4+ T cell-dependent mechanism. Rejection also occurred when cells from chagasic animals were transferred adjacent to hearts transplanted into naive recipients. Here, we observed the formation of a thick laminin network during rejection, with donor-derived CD4+ T cells concentrated in the laminin-rich areas. Most importantly, anti-laminin as well as anti-laminin receptor Ab inhibited the rejection of syngeneic hearts by T cells from chagasic animals. Our results suggest that interaction of the VLA-6 molecule with laminin is involved in triggering the antimyocardial autoreactive process by driving the influx of CD4+ T cells to the heart. They also support the concept that an Ag-specific T cell response, even an autoreactive one, can be modulated by in vivo interactions involving extracellular matrix ligands and receptors. In this regard, our study represents, to our knowledge, the first in vivo evidence for laminin-mediated T cell echotaxis, with simultaneous experimental demonstration of ligand and receptor involvement. Lastly, our findings indicate that treatment with anti-VLA-6 Abs can be effective in suppressing autoimmune disease activity.