Chemoirradiated neutrophils and T cells differentially affect immune functions of APCs

Abstract

Extracorporeal photopheresis (ECP) is known as an immunomodulatory therapy with few side effects, which is mainly used in the treatment of cutaneous T cell lymphoma, graft‐versus‐host disease, and allograft rejection. During ECP, leukocytes are separated from whole blood by leukapheresis, subsequently chemoirradiated with 8‐methoxypsoralen and UVA light, and re‐infused into the patient. Although clinically effective, its mode of action has not been fully elucidated. In the present study, we analyzed the interaction of chemoirradiated neutrophils and CD3+ lymphocytes with APC in an in vitro model. We report that chemoirradiated CD3+ T cells induced increased expression of activation markers on dendritic cells (DC), macrophages, and monocytes. Coculture of chemoirradiated CD3+ T cells with these APC also led to significantly increased secretion of TNF‐α. Although less pronounced, additional activation of APC took place when APC were stimulated with LPS or IFN‐γ. In contrast, chemoirradiated neutrophils did not show activating effects on APC. The presence of chemoirradiated neutrophils during LPS and IFN‐γ stimulation of DC rather diminished DC and macrophage activation. In line with these findings DC cocultured with chemoirradiated CD3+ T cells, but not neutrophils, showed significantly increased activation of CD3+ responder lymphocytes in a mixed lymphocyte reaction. With this study, we demonstrate that chemoirradiated leukocytes have differential indirect immunomodulatory effects. Whereas chemoirradiated CD3+ T cells activate APC, chemoirradiated neutrophils suppress activation of APC in the presence of other activating factors, suggesting that the composition of the ECP‐treated buffy coat might be of importance for its immunomodulatory effects.

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

“… 132 Similar results were observed when culturing chemoirradiated neutrophils with other APCs (i.e., monocytes and macrophages). 132 Overall, the two studies described above 131 , 132 indicate that neutrophils of patients undergoing ECP acquire the capacity to control cGVHD by inhibiting T cells either directly or indirectly by hampering the activation of APCs.…”

“…In the same experimental setting, neutrophils were also found to impair the LPS-induced and IFNγ-induced activation of DCs. 132 Consistently, DCs previously cultured with chemoirradiated neutrophils showed a reduced allostimulatory activity in mixed lymphocyte reaction. 132 Similar results were observed when culturing chemoirradiated neutrophils with other APCs (i.e., monocytes and macrophages).…”

“…Interestingly, subsequent in vitro studies from the same authors 132 demonstrated that 8-MOP- and UVA-treated neutrophils are unable to activate autologous DCs, failing to induce their upregulation of CD80, CD83, and programmed-death ligand 1 (PD-L1) and release of IL-10, TNF-α and IL-12p70. In the same experimental setting, neutrophils were also found to impair the LPS-induced and IFNγ-induced activation of DCs.…”

Increasing the collection flow rate to 2 mL/min is effective and reduces the procedure time in off‐line photopheresis

“…In any case, further studies, taking into account the clinical course of the disease, seem desirable and it remains to be seen what immunomodulatory role will still be attributed to PLT, interleukins, neutrophil granulocytes, and other factors in the future. [27][28][29][30][31][32] Limitations of this study are the small number of patients and of photopheresis procedures.…”

Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)

“…Indeed, recent data suggests that tolerogenic and immunogenic effects can be potentially exerted by different cell types in the same ECP-treated sample since apoptotic neutrophils downregulated LPS-induced DC and macrophage inflammatory cytokine production and reduced overall APC activation. In contrast, co-culture with apoptotic CD3 T-cells activated both APCs and enhanced LPS-induced proinflammatory cytokine production, particularly of TNF-α, coupled with enhanced APC allostimulatory capacity (125).…”