Abstract
There is an unmet clinical need for immunotherapeutic strategies that specifically target the active immune cells participating in the process of rejection after solid organ transplantation. The monocyte–macrophage cell lineage is increasingly recognized as a major player in acute and chronic allograft immunopathology. The dominant presence of cells of this lineage in rejecting allograft tissue is associated with worse graft function and survival. Monocytes and macrophages contribute to alloimmunity via diverse pathways: antigen processing and presentation, costimulation, pro-inflammatory cytokine production, and tissue repair. Cross talk with other recipient immune competent cells and donor endothelial cells leads to amplification of inflammation and a cytolytic response in the graft. Surprisingly, little is known about therapeutic manipulation of the function of cells of the monocyte–macrophage lineage in transplantation by immunosuppressive agents. Although not primarily designed to target monocyte–macrophage lineage cells, multiple categories of currently prescribed immunosuppressive drugs, such as mycophenolate mofetil, mammalian target of rapamycin inhibitors, and calcineurin inhibitors, do have limited inhibitory effects. These effects include diminishing the degree of cytokine production, thereby blocking costimulation and inhibiting the migration of monocytes to the site of rejection. Outside the field of transplantation, some clinical studies have shown that the monoclonal antibodies canakinumab, tocilizumab, and infliximab are effective in inhibiting monocyte functions. Indirect effects have also been shown for simvastatin, a lipid lowering drug, and bromodomain and extra-terminal motif inhibitors that reduce the cytokine production by monocytes–macrophages in patients with diabetes mellitus and rheumatoid arthritis. To date, detailed knowledge concerning the origin, the developmental requirements, and functions of diverse specialized monocyte–macrophage subsets justifies research for therapeutic manipulation. Here, we will discuss the effects of currently prescribed immunosuppressive drugs on monocyte/macrophage features and the future challenges.
Highlights
Solid organ transplantation (SOT) is the preferred method to treat organ failure
This suggests that glucocorticoid therapy in combination with belatacept therapy could theoretically block the immune response by T cells induced via antigen-presenting monocytes after transplantation
Peripheral blood monocytes from healthy donors cultured for 60 h in the presence of different concentrations of sinomenine showed an enhanced production of IL-6 and a decreased expression of IL-8, which is important for cell migration [128]
Summary
Solid organ transplantation (SOT) is the preferred method to treat organ failure. Over the past decades, transplantation has become the preferred approach to treat solid organ failure. Striking improvement in short-term allograft survival, in particular of kidney allograft, has been achieved, while long-term survival has lagged behind [1] This improvement is seen mainly in recipients who have never experienced a rejection episode, thereby emphasizing the recipient’s alloimmunity, in particular chronic antibody-mediated rejection (cABMR) as a major determinant of overall transplant outcome [2, 3]. The clinically used immunosuppressive drugs are not directed against monocyte–macrophage lineage cells but still have some inhibitory effects. These cells contribute to alloimmunity via diverse pathways, antigen processing and antigen presentation, costimulation, pro-inflammatory cytokine production, and tissue repair. To elaborate on the effects of currently available immunosuppressive drugs in relation to monocyte/macrophage lineage cells mainly focused within, and outside of the SOT field (Table 1 and Figure 1), and eventually touch upon the future challenges and developments
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