Pharmacologic recruitment of regulatory T cells as a therapy for ischemic acute kidney injury

Abstract

Regulatory T cells (Tregs) are key components of the peripheral tolerance system and have become an immunotherapeutic agent for treating inflammatory processes. This therapeutic option, however, is hampered by problems arising from isolating and expanding desirable Tregs. Here we used an alternative approach with a pharmacologic agent to stimulate Tregs to achieve immunosuppressive effects. Pretreatment of mice with the naturally occurring sphingosine N, N-dimethylsphingosine (DMS) was found to increases both tissue infiltrating T effectors (Teff, CD4+Foxp3−) and Tregs (CD4+Foxp3+), in the early phase of bilateral renal ischemia/reperfusion injury. DMS itself had no effects on renal function or histopathology, but rapidly and transiently increased both Teff and Tregs and increased the expression of chemokines CXCL9, CCL5, and CXCL10 in non-ischemic kidneys (sham operation). This renoprotection was abolished by administration of the Treg suppressing agents, anti-CTLA-4 or anti-CD25 monoclonal antibodies, suggesting that Tregs play a key role in DMS-induced renoprotection. Thus, Tregs recruited to the kidney by DMS, ameliorate acute kidney injury and provide a new approach to control inflammatory diseases.

Regulatory T Cells in AKI

“…If given 10 minutes before ischemia, DMS protected against IRI, an effect that was negated by prior PC61 treatment to deplete Tregs. 41 DMS is a sphingosine kinase inhibitor; however, another more specific sphingosine kinase inhibitor did not produce similar results, suggesting that the mechanism is an unknown off-target effect. 41 Sphingosine-1-phosphate analog (FTY720) enhanced Treg numbers in the spleen and kidney and protected mice from kidney IRI.…”

“…40 Several recent preclinical studies suggest that other pharmaceutical agents target intrinsic Tregs and may be beneficial in AKI. Lai et al 41 observed rapid and transient trafficking of Tregs into the kidney on administration of dimethylsphingosine (DMS) in mice. If given 10 minutes before ischemia, DMS protected against IRI, an effect that was negated by prior PC61 treatment to deplete Tregs.…”

“…37 Pharmacologic recruitment of Tregs to the kidney before IRI is beneficial in mice treated with isotype control antibodies but not mice treated with a CTLA-4 blocking antibody. 41 CD39, ectonucleoside triphosphate diphosphohydrolase 1; FasL, Fas ligand; LAG-3, Lymphocyte-activation gene 3. *Critical mechanisms used by Tregs in AKI models; most of the other mechanisms depicted have not been tested in these models and may also contribute to Treg function (A).…”

Autocrine Adenosine Signaling Promotes Regulatory T Cell–Mediated Renal Protection

“…29 Whether adoptively transferred Tregs must localize in the kidney to provide protection from IRI is unknown. This study does not provide any information on the site(s) of action for adoptively transferred Tregs; this is currently under investigation.…”

Role of Lymphocytes in Myocardial Injury, Healing, and Remodeling After Myocardial Infarction

“…Indeed, there are reports that Treg activation protects against experimental ischemia-reperfusion injury in other organs, such as the liver 38 and kidney. 39 Most of these studies do not address the exact mode of Treg activation and interaction with innate immune cells, though these phenomena are generally associated with increased Treg levels in the injured organ.…”