Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine that promotes IgA/IgG2b switching and secretion. Here, we show a differential effect of TGF-beta 1 on Ig production by lipopolysaccharide-stimulated spleen and lymph node (LN) B cells. Exogenous TGF-beta 1 increased IgA production in B cell cultures and IgG2b production by spleen B cells. In contrast, IgG2b was suppressed by TGF-beta 1 in cultures of LN B cells, although endogenous TFG-beta was required for IgG2b production in LN B cell cultures. The suppressor properties of exogenous TGF-beta 1 (0.5 ng/ml) on IgG2b production by LN B cells were also seen when testing IgG1 or IgG2a induced by interleukin-4 or interferon-gama, respectively. These differences between B cells from each lymphoid tissue appeared to be related to a different TGF-beta antiproliferative effect, since proliferation of LN B cells was extremely sensitive to TFG-beta 1 and IgG2b production was more sensitive than IgA to the TFG-beta-mediated suppression. However, by counteracting the antiproliferative effect of TGF-beta 1 with a CD40 agonistic mAb (IC10), the IgG2b response by LN B cells was still lacking. IC10 was nevertheless inhibitory for IgG2b production in most cases, while increasing secretion of IgA in the very same cultures. Taken together, the results suggest that functional differences between spleen and LN B cells do exit, at least with regard to the immunomodulating properties of TGF-beta on both proliferation and Ig production. Moreover, functional differences exist between cells committed for IgA and IgG2b regarding their sensitivity to the antiproliferative activity of TGF-beta 1 and the effect of CD40-derived signals on Ig secretion.
Objectives To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018–2021. Methods We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. Results We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30–0.74) compared with dolutegravir/lamivudine. For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. Conclusions In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.
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