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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.

SUBMITTER: van den Bosch TP

PROVIDER: S-EPMC5312419 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Targeting the Monocyte-Macrophage Lineage in Solid Organ Transplantation.

van den Bosch Thierry P P TP Kannegieter Nynke M NM Hesselink Dennis A DA Baan Carla C CC Rowshani Ajda T AT

Frontiers in immunology 20170216

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 alloimmu ...[more]

PMID: 28261211

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Project description:Background and purposePosterior reversible encephalopathy syndrome (PRES) is known to occur after solid organ transplantation (SOT), potentially associated with cyclosporine and tacrolimus. In this study, we assess the frequency and clinical and imaging characteristics of PRES after SOT.Materials and methodsWe identified 27 patients (13 men and 14 women; age range, 22-72 years) who developed PRES after SOT. Features noted included SOT subtype, incidence and timing of PRES, infection and rejection, mean arterial pressure (MAP), and toxicity brain edema.ResultsPRES developed in 21 (0.49%) of 4222 patients who underwent transplantation within the study period (no significant difference among SOT subtypes). Transplantation was performed in 5 patients before the study period, and 1 patient underwent transplantation elsewhere. In consideration of all 27 patients, PRES typically developed in the first 2 months in patients who had SOT of the liver (9 of 10 patients) and was associated with cytomegalovirus (CMV), mild rejection, or systemic bacterial infection. PRES also typically developed after 1 year in patients who had SOT of the kidney (8 of 9 patients) and was associated with moderate rejection or bacterial infection. Toxicity MAP was significantly lower (P < .001) in liver transplants (average MAP, 104.8 +/- 16 mm Hg) compared with that in kidney transplants (average MAP, 143 +/- 20 mm Hg). Toxicity brain edema was significantly greater (P < .001) in patients who had liver transplants and developed PRES compared with patients who had undergone kidney transplants despite severe hypertension in those who had the kidney transplants.ConclusionPatients who had undergone SOTs have a similar low incidence of developing PRES. Differences between those who have had liver and kidney transplants included time after transplant, toxicity MAP, and PRES vasogenic edema noted at presentation. In patients who have undergone kidney transplants, severely elevated MAP was associated with reduced, not greater, brain edema.

Dataset Information

Targeting the Monocyte-Macrophage Lineage in Solid Organ Transplantation.

Publications

Targeting the Monocyte-Macrophage Lineage in Solid Organ Transplantation.

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