Targeting the Monocyte-Macrophage Lineage in Solid Organ Transplantation

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.

Keywords: immunosuppressive drug; macrophage; monocyte; signaling pathways; transplantation.

Figure 1

Monocyte and macrophage lineage cell and the effect of immunosuppressive drugs. The effect of currently prescribed immunosuppressive drugs with several inhibition spots on and in monocyte/macrophage lineage cells.

Figure 2

Monocyte immunobiology. Monocytes arise from myeloid precursor cells in primary lymphoid organs, including liver and bone marrow. In the peripheral blood, monocytes can be subdivided into three distinct subsets according to their CD14 and CD16 expression profile. Monocytes can undergo transendothelial migration through α4β1 integrin interaction with VCAM-1. Activation of monocytes is followed by the polarization of macrophages to acquire pro-inflammatory phenotype (M1), anti-inflammatory phenotype (M2) or the regulatory phenotype (Mreg). The secretion of distinct pro-inflammatory or anti-inflammatory cytokines, next to expression patterns of surface molecules, characterizes each phenotype.

Figure 3

Future challenges and developments: strategies to target monocytes/macrophages. New therapies targeting monocytes and macrophages could intervene at three levels with monocyte actions and their subsequent functions as depicted and described in manuscript body.