Month: November 2017

CLL is a heterogeneous disease with a highly variable clinical course and a number of molecular prognostic markers have been identified to help determine that course. Among these are VLA-4 and CD38, two surface molecules that are believed not only to be mere markers of disease aggressiveness but also to play a role in CLL pathogenesis. VLA-4 is the exclusive member of the a4 integrin subfamily expressed by CLL cells and has recently been identified as a negative prognostic marker in this disease. VLA-4 plays a key role in the retention of hematopoietic progenitors in BM stroma, which is required for normal early B cell development. The second prognostic indicator, CD38, is a promiscuous glycoprotein that functions as an ectoenzyme, a surface receptor, and an adhesion molecule. In CLL, CD38 ligation in the presence of IL-2 induces the survival and proliferation of the tumor cells. Furthermore, CLL cells expressing CD38 are thought to have enhanced migratory capacity. Because VLA-4 and CD38 BAY 73-4506 expression have been described to be highly associated in CLL, we sought to determine their functional consequences in the context of supportive BM niches. For this we employed in vivo adoptive transfers of human leukemic cells into immunodeficient mice, in vitro flow cytometrical phenotyping of peripheral blood – and BM-derived CLL cells, and stromal cell co-culture experiments. Moreover, the extent of BM infiltration in CLL patients was correlated to the VLA-4 and CD38 status. Our data suggest that VLA-4 but not CD38 expression plays a prominent role in the homing of high-risk CLL cells to supportive BM niches and in human BM infiltration but only a limited role in supportive CLL cell-stromal cell interactions in vitro. Emerging evidence suggests that the proliferation and survival of CLL cells is dependent on their interplay with accessory cells and molecular factors in supportive niches. It is therefore essential to define the molecular mechanisms underlying the trafficking of CLL cells into these niches. Among the plenitude of prognostic markers supposed to have a pathophysiological influence, VLA-4 and CD38 may be key players regulating tissue invasion and infiltration in CLL. Since the majority of CLL samples show associated VLA-4 and CD38 expression, their individual roles in CLL cell migration and interactions with supportive accessory cells are still unclear. Therefore, in this study, we particularly analyzed samples with discordant VLA-4/CD38 expression. Collectively, our data argue for a higher propensity of high-risk CLL cells to infiltrate supportive BM niches as a result of their VLA-4 rather than CD38 expression, but only a limited role of VLA-4 in malignant cell-GSK212 stroma interactions.

Preliminary results demonstrate that a specific blocker of CCR5 and CCR1 chemokine receptors, called met-RANTES, was able to decrease the experimental PD severity. However the mechanisms involved in such modulation, the ideal dose of met- RANTES to achieve the maximum remission of experimental PD, as well potential side effects concerning the infectious aspects of the disease remain unknown. Therefore, we initially performed a dose-response analysis of experimental PD outcome following met-RANTES therapy. The alveolar bone loss and inflammatory cell influx were used as the disease severity parameters, and the bacterial load in the periodontal tissues was used to monitor the control of infection. Except for the 0.05 mg dose, all the other doses resulted in a significant decrease of experimental PD severity. Interestingly, as a general rule a dose-response effect was identified in the attenuation of inflammatory cells influx, while a Kinase Inhibitor Library similar inhibition of bone resorption was achieved with the doses ranging from 0.5 up to 5 mg. The effectiveness of the met-RANTES in the control of inflammation-associated tissue damage is in agreement with previous studies , but deeper TWS119 comparisons with other models are impaired by the relatively low number of previous studies, performed in quite different experimental models usually investigating one or at most two different met-RANTES doses within a narrow interval. Interestingly, the PD treatment with 5 mg of met-RANTES dose impaired the control of periodontal infection, evidencing to distinct situations, where similar protective effects from the tissue destruction viewpoint are associated with distinct infectious outcomes. Therefore, in order to investigate the mechanisms underlying such differential response, the experimental groups receiving met-RANTES doses of 0.5 and 5 mg were selected for the further analysis. The first scenario, represented by the 0.5 mg met-RANTES protocol, can be interpreted as a clinically desired situation, where the tissue damage was minimized without interfering with host defense process. In fact, the 0.5 mg met-RANTES dose was effective in reducing F4/80 and CD3 cells , which present CCR1 and CCR5 receptor in its membranes, and also was observed a reduction in the tissue levels of pro-inflammatory cytokines IL-1b, TNF-a and IL-6. These cytokines are classically implicated in the onset and progression of PD by its role in osteoclastogenic process , being the reduction in its levels compatible with the attenuation of the experimental disease severity observed. Accordingly, met- RANTES therapy target cells from the monocytic lineage, characteristic sources of IL-1b, TNF-a and IL-6.