A review led by Professors Malgorzata Kloc and Xian Chang Li at the Immunobiology and Transplant Science Center of Houston Methodist Hospital was published in Volume 2, article number 29 of the journal Immunity & Inflammation on June 30, 2026. The article systematically examines the origins, subsets, and functional diversity of macrophages, highlighting their central role as drivers of chronic transplant rejection.
The review outlines that while organ transplantation remains the most effective treatment for end-stage organ failure, long-term graft survival continues to be a significant clinical challenge. T cell-centered immunosuppressive regimens are effective at controlling acute rejection; however, most grafts eventually fail due to chronic rejection. The authors report that massive infiltration of macrophages and other innate immune cells—accompanied by fibrotic changes—is one of the main pathological features seen in chronic rejection cases.
According to the review, macrophages are among the oldest immune system cells. Their core function—phagocytosis—relies on actin and cytoskeletal dynamics similar to those found in single-celled amoebas. Over time, these cells have evolved from simple scavengers into versatile agents with phagocytic, antigen-presenting, and immunomodulatory functions. In transplantation scenarios, this allows them to sense graft injury early on and contribute significantly to vascular pathology and tissue fibrosis during chronic rejection.
The authors state that classifying macrophages solely as pro-inflammatory M1 or pro-repair M2 is overly simplistic. Tissue-resident macrophages derived from yolk sac origins play key roles in homeostasis but can be replaced by recipient-derived monocytes after transplantation. Donor-resident cardiac allograft macrophage subtypes may have opposing effects on graft survival; not all are detrimental. Regulatory macrophages (Mreg) have shown potential benefits by secreting IL-10 and promoting regulatory T cell differentiation.
"Based on the central role of macrophages in chronic rejection, several emerging therapeutic strategies are now under investigation," the authors pointed out. These include targeting purinergic pathways such as P2X7 receptors with inhibitors; modulating mTOR/NF-κB signaling using nanoparticle-delivered inhibitors; inhibiting BRD4 within BET family epigenetic regulators; and repurposing FDA-approved ROCK inhibitors like belumosudil for use against fibrosis-related pathways.
Advances in therapy require improved diagnostics beyond traditional invasive biopsies. Liquid biopsy technologies—including donor-derived cell-free DNA analysis—and spatiotemporal transcriptomics offer new non-invasive methods for monitoring graft health and localizing specific immune responses within transplanted organs.
"As understanding of macrophage heterogeneity, plasticity, and newly discovered functions continues to advance, macrophage-targeted strategies offer promise for overcoming the limitations of current T cell-centered regimens and ultimately achieving long-term graft survival," the authors concluded.
