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Commentary

The promise of immune cell therapy for acute kidney injury

Hamid Rabb

Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Address correspondence to: Hamid Rabb, Ross 965, The Johns Hopkins Hospital, 720 Rutland Ave., Baltimore, Maryland 21205, USA. Phone: 410.502.1556; Fax: 410.614.1643; E-mail: hrabb1@jhmi.edu.

First published October 24, 2012

Acute kidney injury (AKI) often results from ischemia reperfusion, sepsis, or exposure to nephrotoxins and is associated with a high rate of mortality and morbidity. Advances in understanding the pathophysiology of AKI may lead to the development of specific therapies. Although there is evidence of an important role for immune cells in AKI, the specific relevant populations and the mechanisms of their actions are unclear. In this issue of the JCI, Li et al. demonstrate that adenosine manipulates DC responses to kidney injury, raising hope that immunotherapy could be a tangible approach to AKI.

See the related article beginning on page 3931.

Immune cells in acute kidney injury

Acute kidney injury (AKI) occurs in 3%–7% of patients admitted to tertiary care hospitals in industrialized nations (1). In native kidneys, AKI-associated mortality approaches 50% when occurring in the intensive care unit, and AKI in allograft kidneys worsens short- and long-term kidney function. Ischemia/reperfusion injury (IRI) is a common cause, as are sepsis and nephrotoxins. There is no specific therapy except for supportive care and dialysis. While much of the initial work on AKI pathophysiology focused on the highly abundant epithelial cell, more recent studies have revealed an important role for immune, endothelial, and peritubular resident cells (2). The evidence for the role of immune cells emerged from studies showing that leukocyte adhesion molecules (LAMs) mediated AKI; however, many of the beneficial effects were independent of neutrophils being targeted by LAMs, which was initially confusing (35). Further studies demonstrated that T cells were activated during AKI, migrated to kidney, and directly mediated tissue injury (6). This opened up the possibility of other immune populations such as DCs and NKT cells participating in AKI (ref. 7 and Figure 1). Work in other organs, such as lung, liver, and brain, has also revealed the engagement and participation of traditional immune cells in alloantigen-independent acute tissue injury (2, 8).

Immune cells in AKI.Figure 1

Immune cells in AKI.Immune cells likely mediate AKI while in circulation and when localized in the renal microvasculature, renal interstitium, and lymphoid tissue. While in the renal microcirculation during reperfusion, these cells increase their adhesiveness and adhere to activated endothelium and other cells, accentuating the “plug” that contributes to the no-reflow phenomenon. Some immune cells migrate into the interstitium, but there are also well-described resident renal immune cells. T and B cell, DC, NK and NKT cell, macrophage, and neutrophil crosstalk accentuates the postischemic inflammation. These cells produce and respond to cytokines, chemokines, oxygen free radicals, complement, coagulant factors, and other mediators. Adenosine, acting via A2AR, activates DCs, which in turn modulate NKT cell function by decreasing IFN-γ secretion. This triggers increased IL-10 levels, which subsequently downregulate postischemic inflammation. Panels depict the outer medulla. Adapted with permission from the Journal of Molecular Medicine (2).

Adenosine receptor 2A agonist-induced tolerogenic DCs in AKI

Adenosine, a breakdown product of ATP/ADP metabolism that accumulates in AKI, has been known to regulate lymphocyte responses and is thus an attractive target for modulating immune cells and improving outcomes in AKI (9). In the current issue of JCI, Li et al. have elegantly demonstrated that DCs can be modulated by adenosine or selective adenosine receptor agonists to improve the course of AKI when administered prior to or at the time of ischemic injury (10). Li et al. found that kidney dysfunction and inflammation after IRI were accentuated in mice deficient in the adenosine receptor A2AR only on CD11c+ DCs, while selective A2AR agonist ATL313 administration led to tissue protection. Studying bone marrow-derived DCs primed with the glycolipid antigen α-galactosylceramide (αGC) to activate NKT cells led to a worsening of kidney dysfunction after mild (26 minutes) ischemia. Treating DCs that were primed with the NKT agonist αGC with adenosine receptor agonist protected from AKI. The DC therapy was effective if given 2 or 7 days prior to ischemic injury, or at 1 or 6 hours after injury, but not when started 24 hours after IRI. This finding indicates that modified DC cell therapy could be applied for prevention and early treatment; however, most patients are diagnosed well after ischemic injury, so the lack of effect when given 24 hours after ischemia may limit its practical application.

A key mechanism by which adenosine-mediated DC cell therapy works in AKI appears to be via IL-10, a powerful antiinflammatory cytokine. IL-10 increased in kidney after adenosine-stimulated DC therapy, and blocking endogenous IL-10 reversed the protective effect. Furthermore, administering adenosine-stimulated DC therapy to IL-10–deficient mice led to a loss of the protective effect of the DCs, clearly implicating IL-10 as a protective mechanism (10). This finding is in line with previous reports showing that IL-10 is an important protective cytokine in AKI (11).

Therapeutic implications

The current study is built on a large body of work regarding the promise of tolerogenic DC cell therapy for human disease. Given that the adenosine-induced DCs were effective prior to AKI and up to 6 hours after, this would seem to be a useful approach for prevention of serious injury. However, most patients are diagnosed with AKI at least 12–24 hours after the ischemic insult. The best clinically available marker for AKI is a rise in serum creatinine, which occurs late and can be insensitive. Using improved biomarkers such as KIM-1, NGAL, IL-18, FABP, and Gro-α are potential ways to diagnose AKI early in order to enable timely administration of therapeutic agents (1214). However, in the absence of earlier markers, cell therapy would be most useful if it could be used during established AKI. Another immune cell population, CD25+FoxP3+ Tregs, are an exciting candidate for cell therapy, since these cells are effective even when administered 24 hours after the ischemic insult and may also work via IL-10–mediated decreased inflammation and enhanced repair (15). Delivery of exogenous stem cells also shows great promise during established AKI (16). Even though repopulation of tubular epithelial cells after AKI is probably due to division of cells already resident in the kidney rather than from bone marrow–derived cells (17), administration of stem cells could increase the proliferation of the resident cells by paracrine mechanisms and factors including IL-6, SDF-1, and VEGF (18).

In the broader context, many patients with AKI harbor infections in addition to a “sterile” systemic inflammation from the kidney dysfunction, leading to inflammation in distant organs (19). Thus, dampening the immune system with cell therapy during AKI has to be balanced, as is the case in any immunosuppressive approach, with the risk of increasing the susceptibility to infection. Another possibility that has not been well studied in the experimental literature is that inflammation during AKI, though initially deleterious, could be important in repair. Thus interfering with early inflammation could ironically lead to more fibrosis long term, resulting in increased risk after an episode of AKI for development of chronic kidney disease (CKD) rather than full recovery.

Unanswered questions

The current study by Li et al. sheds light on exciting mechanistic pathways during ischemic AKI and stimulates many other questions. The location of the effect of the adenosine-stimulated DCs could be intrarenal or extrarenal, including in lymph nodes. The recognition of IL-10 as a key mediator of these effects raises the question of the identity of the cell producing IL-10, since it is probably not the DCs themselves. Are all of the effects due to IL-10, and if so, could IL-10 be infused at an appropriate dose and time in the place of cell therapy? Furthermore, what are the early signals that engage DCs in AKI as well as activate the other related immune pathways? Since T cells are known to modulate outcomes in AKI, either in a deleterious or protective way, depending on their functional subtype (20), a key question is what the initial stimulus is for such a rapid response in the absence of alloantigen. To date, no AKI antigen has been identified as driving immune responses. One of the confusing findings has been that many different immune cells are known to mediate AKI, but their relationships with each other, their redundancies, and molecular mechanisms underlying their roles in kidney injury and repair are largely unknown.

Furthermore, ischemic injury, the focus of the Li et al. paper, may not have the same pathophysiologic pathways as nephrotoxic injury or sepsis. Another key step will be to understand why so many mechanistic studies in rodents have shown protection while clinical studies targeting the same pathways have failed. Does ischemic injury in native kidneys have a different pathophysiology than IRI in allografts when additional factors such as brain death, cold transport, and immunosuppressive treatment are superimposed? Finally, a recent surge of data has identified AKI as an important risk factor for CKD (2123), and immune cells are likely important mediators between these two diseases, possibly related to autoimmunity (24). The type of immune cells involved in AKI-to-CKD transition and the details of how they function will be important to elucidate.

Acknowledgments

This work was supported by grants from the NIH, the National Kidney Foundation, and the American Heart Association. Sanjeev Noel graciously assisted with the figure.

Footnotes

Conflict of interest: The author has declared that no conflict of interest exists.

Citation for this article:J Clin Invest. 2012;122(11):3852–3854. doi:10.1172/JCI66455.

See the related article beginning on page 3931.

References

  1. Clarkson MR, Friedewald JJ, Eustace JA, Rabb H. Acute kidney injury. In: Brenner BM, ed. Brenner & Rector’s The Kidney.8th ed. Philadelphia, Pennsylvania, USA: Saunders, Elsevier; 2008;:943–986.
  2. Jang HR, Ko GJ, Wasowska BA, Rabb H. The interaction between ischemia-reperfusion and immune responses in the kidney. J Mol Med. 2009;87(9):859–864.
    View this article via: PubMed CrossRef
  3. Thornton MA, Winn R, Alpers CE, Zager RA. An evaluation of the neutrophil as a mediator of in vivo renal ischemic-reperfusion injury. Am J Pathol. 1989;135(3):509–515.
    View this article via: PubMed
  4. Rabb H, et al. Role of CD11a and CD11b in ischemic acute renal failure in rats. Am J Physiol. 1994;267(6 pt 2):F1052–F1058.
    View this article via: PubMed
  5. Kelly KJ, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest. 1996;97(4):1056–1063.
    View this article via: JCI.org PubMed CrossRef
  6. Burne MJ, et al. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest. 2001;108(9):1283–1290.
    View this article via: JCI.org PubMed
  7. Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia–reperfusion injury. Kidney Int. 2007;71(7):619–628.
    View this article via: PubMed CrossRef
  8. Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant. 2011;11(8):1563–1569.
    View this article via: PubMed CrossRef
  9. Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997;90(4):1600–1610.
    View this article via: PubMed
  10. Li L, et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J Clin Invest. 2012;122(11):3931–3942.
    View this article via: JCI.org CrossRef
  11. Deng J, et al. Star Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 2001;60(6):2118–2128.
    View this article via: PubMed CrossRef
  12. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010;28(5):436–440.
    View this article via: PubMed CrossRef
  13. Mishra J, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231–1238.
    View this article via: PubMed CrossRef
  14. Molls RR, et al. Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol. 2006;290(5):F1187–F1193.
    View this article via: PubMed CrossRef
  15. Gandolfo MT, et al. Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int. 2009;76(7):717–729.
    View this article via: PubMed CrossRef
  16. Tögel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289(1):F31–F42.
    View this article via: PubMed CrossRef
  17. Humphreys BD, et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008;2(3):284–291.
    View this article via: PubMed CrossRef
  18. Huang Y, et al. Kidney-derived stromal cells modulate dendritic and T cell responses. J Am Soc Nephrol. 2009;20(4):831–841.
    View this article via: PubMed CrossRef
  19. Grams ME, Rabb H. The distant organ effects of acute kidney injury. Kidney Int. 2012;81(10):942–948.
    View this article via: PubMed CrossRef
  20. Yokota N, Burne-Taney M, Racusen L, Rabb H. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2003;285(2):F319–F325.
    View this article via: PubMed
  21. Ishani A, et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol. 2009;20(1):223–228.
    View this article via: PubMed CrossRef
  22. Macedo E, Bouchard J, Mehta RL. Renal recovery following acute kidney injury. Curr Opin Crit Care. 2008;14(6):660–665.
    View this article via: PubMed CrossRef
  23. Cohen SD, Kimmel PL. Long-term sequelae of acute kidney injury in the ICU [published online ahead of print August 29, 2012]. Curr Opin Crit Care. doi: 10.1097/MCC.0b013e328358d3f5 .
    View this article via: PubMed CrossRef
  24. Burne-Taney MJ, Liu M, Ascon D, Molls RR, Racusen L, Rabb H. Transfer of lymphocytes from mice with renal ischemia can induce albuminuria in naive mice: a possible mechanism linking early injury and progressive renal disease? Am J Physiol Renal Physiol. 2006;291(5):F981–F986.
    View this article via: PubMed CrossRef
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