Mesenchymal stem cells, autoimmunity and rheumatoid arthritis

The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow-derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Pre-clinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord-derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and systemic lupus erythromatosis. The potential use of bone marrow-MSC (BM-MSC) for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell-cultured progeny termed fibroblast-like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC-based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles

Adverse effect of abdominal operations on production of interferon-gamma.

peer reviewed[en] OBJECTIVE: To assess the effects of abdominal operations on the production of cytokines as one of the mechanisms of postoperative immunosuppression. DESIGN: Prospective study. SETTING: University hospital, Belgium. SUBJECTS: 19 Selected patients who underwent operations for benign (n = 10) or malignant (n = 9) diseases. INTERVENTIONS: Whole blood was collected in heparinised tubes before operation and on postoperative days 1, 2, 3, 5, 7, and 9. After 1/10 dilution in culture medium the whole blood cells were stimulated with 5 micrograms/ml phytohaemagglutinin and 25 micrograms/ml lipopolysaccharide, and incubated at 37 degrees C in 5% carbon dioxide. Concentrations of interleukin 1 (IL-1), tumour necrosis factor alpha (TNF alpha), and interleukin 6 (IL-6) were measured at 24 hours, and interferon-gamma and interleukin 2 (IL-2) were measured at 72 hours, with commercially available assays. OUTCOME MEASURES: Production of the monokines IL-1, TNF alpha, and IL-6, and of the lymphokines IL-2 and interferon-gamma, postoperatively. The monokines were expressed as a percentage of the preoperative values/monocyte, and the lymphokines as a percentage of preoperative values/lymphocyte. RESULTS: Production of IL-1 and TNF alpha, but not IL-6, decreased immediately after operation then returned to preoperative values. Production of IL-2 and interferon-gamma were significantly reduced immediately after operation, and that of interferon-gamma was still depressed on the ninth postoperative day. CONCLUSION: Cytokine production is altered after abdominal operations. The production of interferon-gamma may be a more sensitive indicator of altered immune response and vulnerability to infections and tumour growth than concentrations of other cytokines

Nitric oxide short-circuits interleukin-12-mediated tumor regression

Interleukin-12 (IL-12) can promote tumor regression via activation of multiple lymphocytic and myelocytic eVectors. Whereas the cytotoxic mechanisms employed by T/NK/NKT cells in IL-12-mediated tumor kill are well deWned, the antitumor role of macrophage-produced cytotoxic metabolites has been more controversial. To this end, we investigated the speciWc role of nitric oxide (NO), a major macrophage eVector molecule, in post-IL-12 tumor regression. Analysis of tumors following a single intratumoral injection of slow-release IL-12 microspheres showed an IFN-dependent sevenfold increase in inducible nitric oxide synthase (iNOS) expression within 48 h. Flow cytometric analysis of tumor-resident leukocytes and in vivo depletion studies identiWed CD11b+ F4/80+ Gr1lo macrophages as the primary source of iNOS. Blocking of post-therapy iNOS activity with N-nitro-L-arginine methyl ester (L-NAME)dramatically enhanced tumor suppression revealing the inhibitory eVect of NO on IL-12-driven antitumor immunity. Superior tumor regression in mice receiving combination treatment was associated with enhanced survival and proliferation of activated tumor-resident CD8+ T-eVector/memory cells (Tem). These Wndings demonstrate that macrophageproduced NO negatively regulates the antitumor activity of IL-12 via its detrimental eVects on CD8+ T cells and identify L-NAME as a potent adjuvant in IL-12 therapy of cancer

Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells

NO inhibits cytotoxic T lymphocyte killing of target cells, although the precise mechanism is unknown. We hypothesized that NO decreases exocytosis of cytotoxic granules from activated lymphocytes. We now show that NO inhibits lymphokine-activated killer cell killing of K562 target cells. Exogenous and endogenous NO decreases the release of granzyme B, granzyme A, and perforin: all contents of cytotoxic granules. NO inhibits the signal transduction cascade initiated by cross-linking of the T cell receptor that leads to granule exocytosis. In particular, we found that NO decreases the expression of Ras, a critical signaling component within the exocytic pathway. Ectopic expression of Ras prevents NO inhibition of exocytosis. Our data suggest that Ras mediates NO inhibition of lymphocyte cytotoxicity and emphasize that alterations in the cellular redox state may regulate the exocytic signaling pathway