Rituxan in ANCA-associated vasculitis

Wegener’s granulomatosis and microscopic polyangiitis are classified as antineutrophil cytoplasmic antibody (ANCA)−associated vasculitides as most patients have antibodies against proteinase 3 or myeloperoxidase.The ANCA-associated vasculitides affect small-to-medium-size blood vessels, with a predilection for the respiratory tract and kidneys. Without treatment mortality is very high and mostly the norm.

Cyclophosphamide and glucocorticoids have been the standard therapy for remission induction for decades. While this treatment is effective in controlling the disease and inducing temporary remission in a majority of the patients, the side effects of cyclophosphamide (leucopenia, infertility, bladder cancer) are very severe and limiting. And, a search for a suitable alternative to cyclophosphamide for inducing disease remission in these patients with fewer side effects is ongoing.

In the following slides I have summarized two landmark studies that evaluated Rituxan in ANCA associated vasculitis as an alternative to cyclophosphamide:

Virological Synapses Allow HIV-1 Uptake and Gene Expression in Renal Tubular Epithelial Cells.

Authors:
Chen P, Chen BK, Mosoian A, Hays T, Ross MJ, Klotman PE, Klotman ME.

Reference:
J Am Soc Nephrol. 2011 Mar;22(3):496-507. Epub 2011 Feb 18.

Abstract:
In animal models of HIV-associated nephropathy, the expression of HIV regulatory genes in epithelial cells is sufficient to cause disease, but how the CD4-negative epithelial cells come to express HIV genes is unknown. Here, we co-cultured T cells infected with fluorescently tagged HIV with renal tubular epithelial cells and observed efficient virus transfer between these cells. The quantity of HIV transferred was much greater than that achieved by exposure to large amounts of cell-free virus and occurred without a requirement for CD4 or Env. The transfer required stable cell-cell adhesion, which could be blocked by sulfated polysaccharides or poly-anionic compounds. We found that the internalization of virus could lead to de novo synthesis of viral protein from incoming viral RNAs even in the presence of a reverse transcriptase inhibitor. These results illustrate an interaction between infected T cells and nonimmune cells, supporting the presence of virological synapses between HIV-harboring T cells and renal tubular epithelial cells, allowing viral uptake and gene expression in epithelial cells.

HIV Entry Into Renal Tubular Epithelial Cells Through Cell–Cell Adhesion

Using live confocal imaging, Chen et al followed interactions between renal tubular epithelial cells (RTECs) and co-cultured fluorescently-tagged-HIV infected CD4+ T cells and recently demonstrated that the viral RNA was directly transferred from the infected CD4+ T cells into RTECs. The virus transfer required cell surface heparin sulfate proteoglycans (which serve as attachment receptors for HIV-1 on macrophages and dendritic cells) and stable cell–cell adhesion and was independent of HIV Env expression. Interestingly, the quantity of viral RNA transferred through cell–cell adhesion was much higher than that achieved by exposure large amounts of cell-free virus.

The authors also demonstrated that the HIV virus acquired via cell–cell contact results in de novo synthesis of viral proteins in the infected RTECs. Furthermore, reverse transcriptase, protease and integrase inhibitors seem to block gene expression in the RTECs that acquired the infection from cell-free virus but not in the RTECs that acquired the virus via cell–cell contact.

In summary, it seems that direct transfer of virus from infected T cells to RTECs is possible in vitro on cell–cell contact via a highly efficient mechanism that is independent of Env. The extent to which this happens in vivo and contributes to the pathogenesis of HIV-associated nephropathy remains to be seen.

Reference: chen et al. J Am Soc Nephrol. 2011 Mar;22(3):496-507. Epub 2011 Feb 18.