Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection.

Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year posttransplant, chronic rejection (CR) remains a significant barrier to long-term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion and progressive loss of graft function. Multiple factors have been implicated in the onset and progression of CR, including TGFbeta, IL-6 and connective tissue growth factor (CTGF). While associated with CR, the role of CTGF in CR and the factors necessary for CTGF induction in vivo are not understood. To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGFbeta transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization whereas TGFbeta expression remained unchanged, indicating that IL-6 effects may potentiate TGFbeta-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGFbeta and IL-6 expression levels. These findings indicate that CTGF functions as a downstream mediator of fibrosis in CR, and that CTGF neutralization may ameliorate fibrosis and hypertrophy associated with CR.

Distal IgA immunity can be sustained by alphaEbeta7+ B cells in L-selectin-/- mice following oral immunization.

Understanding the role of homing receptors could aid vaccine strategies for developing distal mucosal immunity. Infection studies have revealed that immune intestinal B cells use alpha(4)beta(7) homing receptors, but their role in subsequent oral immunization with soluble antigens is unknown. To assess the influence of L-selectin and alpha(4)beta(7) on distal B cells following oral cholera toxin (CT) immunization, L-selectin-deficient (L-Sel(-/-)) IgA anti-CT-B-specific B cells were enhanced 30-, 9.2-, and 3.5-fold in head and neck lymph nodes (HNLNs), nasal-associated lymphoid tissue, and nasal passages (NPs), respectively, vs. L-Sel(+/+) mice. Cell-sorted intestinal and NP IgA antibody-forming cells (AFCs) were mostly alpha(4)beta(7)(+), unlike HNLN L-Sel(-/-) IgA and IgG anti-CT-B AFCs that were alpha(E)beta(7)(+), contrasting with L-Sel(+/+) HNLN IgA AFCs that were mostly alpha(4)beta(7)(+). In vitro studies revealed that L-Sel(-/-) HNLN B cells preferentially expressed alpha(E) following polyclonal stimulation. These studies show that HNLN B cells express alpha(E)beta(7) in the absence of L-selectin to sustain distal IgA responses.