Macrophages and Kidney Transplantation

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Summary

Macrophages are present within the transplanted kidney in varying numbers throughout its lifespan. Because of their prominence during acute rejection episodes, macrophages traditionally have been viewed as contributors to T-cell–directed graft injury. With growing appreciation of macrophage biology, it has become evident that different types of macrophages exist within the kidney, subserving a range of functions that include promotion or attenuation of inflammation, participation in innate and adaptive immune responses, and mediation of tissue injury and fibrosis, as well as tissue repair. A deeper understanding of how macrophages accumulate within the kidney and of what factors control their differentiation and function may identify novel therapeutic targets in transplantation.

Section snippets

Phenotypic and Functional Diversity of Monocytes and Macrophages

Monocyte and macrophage biology is reviewed on page 216 in this issue of Seminars in Nephrology1 and will be discussed here only briefly. Circulating bone marrow–derived monocytes exist in subsets that are characterized by unique sets of cell surface markers. Human monocytes may be separated into CD16+ or CD16− subsets with CD16− monocytes expressing the chemokine receptors CCR1 and CCR2. Circulating murine monocytes also may be separated into 2 discrete populations with different chemokine

Macrophage Participation in Kidney IRI and the Importance of IRI in the Development of Acute Rejection

As an essential initial event in the process of kidney transplantation, kidney retrieval, preservation, transportation, and implantation impart an unavoidable episode of IRI. This response has been relatively well characterized in experimental models and is known to be mediated by engagement of endogenous ligands, expressed in response to IRI, by innate immune receptors such as TLRs expressed by kidney parenchymal cells and cells of bone-marrow origin, such as macrophages.16, 17, 18 Evidence

Macrophages in Acute Kidney Allograft Rejection

The initial descriptions of experimental allograft rejection by Brent et al39 in 1958 noted the accumulation of macrophages and T cells in a delayed-type hypersensitivity–like response. In kidney transplantation, a small number of resident tissue macrophages of donor origin are transplanted with the graft.40 Macrophages accumulate within the kidney in response to IRI and then taper after 7 to 14 days to low numbers.41 Although such passenger macrophages may proliferate after implantation,40 the

Role of Macrophages as Mediators of Kidney Inflammation and Damage During Acute Rejection

Several potential roles exist for macrophages during acute rejection including phagocytosis, processing and presentation of antigen to primed CD4+ T cells, proinflammatory cytokine production, effector cell functions causing tissue damage, and finally immune modulation and the promotion of tissue repair. It is likely that such diverse functions are conducted by phenotypically distinct subpopulations of macrophages within the graft.

Anti-Inflammatory and Immunosuppressant Activity of Macrophages Within the Kidney

Macrophages may be deactivated by innate stimuli such as uptake of apoptotic cells, cytokines such as IL-10, TGF-β, and IFN-α/β, as well as therapeutic agents such as glucocorticoids.1, 5, 7, 9, 86 Furthermore, macrophage deactivation may promote differentiation into immunoregulatory macrophages, characterized by low-level expression of MHC class II but high level production of key anti-inflammatory cytokines including IL-10 and TGF-β.1, 7, 9

Although it is highly likely that macrophages are

Macrophages in Chronic Allograft Nephropathy

Although acute rejection is a common event and a significant contributor to graft loss during the first postoperative year, CAN characterized by interstitial fibrosis and tubular atrophy is a far greater cause of graft loss overall.87 The pathogenesis of CAN remains unclear, however, inflammation, mediated via allo-specific (true chronic rejection) and nonspecific (drug toxicity, ischemia) pathways, is a constant feature.88 Macrophage infiltration is a feature of alloimmunity, but may be

Macrophages in Transplant-Associated Lymphangiogenesis

The lymphatic vessels draining the normal kidney are disrupted during organ retrieval with no attempt made to reconnect them surgically to the lymphatic system of the recipient. Early work in dogs suggested that the transplanted kidney effectively becomes reconnected to the systemic lymphatic system within 2 weeks102 and this is important for tubulointerstitial tissue homeostasis.103 More recent work using specific markers for the lymphatic endothelium has shown significant interstitial

Conclusions and Future Prospects

Macrophages are a major presence within the transplanted kidney. Different types of macrophage involvement have been shown at various stages of the allograft response. These include contributions to the innate immune response to renal IRI, effector cell function causing cell damage, and inflammation and the facilitation of adaptive immune responses. In addition, macrophages may promote healing and repair as the graft recovers from acute insults and be involved in the detrimental development of

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    Professor Chadban and Dr Wu receive research funding from the National Health and Medical Research Council of Australia; and Dr Hughes is supported by funding from the UK Medical Research Council, Kidney Research UK, and the Genzyme Renal Innovation Program.

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