Plasmacytoid dendritic cells play a major role in apoptotic leukocyte-induced immune modulation.

Several APCs participate in apoptotic cell-induced immune modulation. Whether plasmacytoid dendritic cells (PDCs) are involved in this process has not yet been characterized. Using a mouse model of allogeneic bone marrow engraftment, we demonstrated that donor bone marrow PDCs are required for both donor apoptotic cell-induced engraftment and regulatory T cell (Treg) increase. We confirmed in naive mice receiving i.v. syngeneic apoptotic cell infusion that PDCs from the spleen induce ex vivo Treg commitment. We showed that PDCs did not interact directly with apoptotic cells. In contrast, in vivo macrophage depletion experiments using clodronate-loaded liposome infusion and coculture experiments with supernatant from macrophages incubated with apoptotic cells showed that PDCs required macrophage-derived soluble factors--including TGF-ß--to exert their immunomodulatory functions. Overall, PDCs may be considered as the major APC involved in Treg stimulation/generation in the setting of an immunosuppressive environment obtained by apoptotic cell infusion. These findings show that like other APCs, PDC functions are influenced, at least indirectly, by exposure to blood-borne apoptotic cells. This might correspond with an additional mechanism preventing unwanted immune responses against self-antigens clustered at the cell surface of apoptotic cells occurring during normal cell turnover.

Defining preoperative treatment strategies in t3 rectal cancer.

Preoperative treatments for patients with T3 rectal cancer have significantly improved local recurrence rates, while survival outcomes have not changed significantly relative to those achieved with surgery alone. The prognosis of patients with T3 tumors, however, is heterogeneous; therapy should be carefully selected based on characteristics of the tumor and other prognostic indices to provide an optimal outcome for each patient. This paper summarizes key findings from several large trials that have examined use of preoperative radiotherapy and chemoradiotherapy for rectal cancer, how these results can be applied to selection of the best therapy for an individual patient, as well as prognostic/predictive factors that have been identified and clinical tools for measuring them.