Acute kidney injury (AKI) is associated with a high mortality in native kidneys, decreased allograft survival in transplants, and very high health care costs. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI). Despite advances in medical care, the mortality and morbidity associated with AKI after IRI remain high, with no specific therapy. A major unknown is the role of different T cell types in either causing/preventing tissue damage or improving/worsening repair. Detailed understanding of the roles of different T cell types holds great promise in both elucidating mechanisms underlying IRI and also in devising new strategies to ameliorate AKI. One such strategy is to shift the T cell balance in favor of protective T cell types and away from pathogenic ones. Therefore, it is important to study different T cell types residing and trafficking to the kidney and investigate their roles in the steady state and IR conditions. Our team has had a long-standing interest in studying immune cells in AKI using experimental animal models with translational potential. We recently discovered a unique population of CD4-CD8- double negative (DN) CD3+TCRab+ T cells that occupies a large niche of the ab T cell compartment in the normal mouse kidney and undergoes marked changes during AKI. However, their functions in the normal kidney and AKI pathogenesis remain relatively unknown. Based on strong preliminary data on DN cells, our overarching hypothesis is that kidney DN T cells play a major and unique role in regulating renal immune cell homeostasis in the steady state and after AKI.
Our specific Aims are: 1) Investigate mechanisms and significance of steady state proliferation of kidney DN T cells. 2) Investigate immunoreactivity of DN T cells to IRI induced AKI. 3) Test the ability of DN T cells to prevent AKI and/or accelerate repair using gain and loss-of-function strategies. Establishing a functional role for this previously unappreciated cell type in the kidney will substantially advance our understanding of the kidney immunology and could lead to paradigm shifting scientific concepts.

Public Health Relevance

Immune cells are major players in ischemia reperfusion injury (IRI), a major problem in both native and transplanted kidneys. Our studies are expected to uncover the function of a novel T cell subset that resides in significant numbers in the normal kidney but whose function is poorly understood. The results can lead to new therapeutics to decrease injury and inflammation after kidney IRI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104662-03
Application #
9236186
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (06))
Program Officer
Kimmel, Paul
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$327,623
Indirect Cost
$120,389
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Lee, Sul A; Noel, Sanjeev; Sadasivam, Mohanraj et al. (2017) Role of Immune Cells in Acute Kidney Injury and Repair. Nephron :
Noel, Sanjeev; Desai, Niraj M; Hamad, Abdel Rahim A et al. (2016) Sex and the single transplanted kidney. J Clin Invest 126:1643-5
Martina, Maria N; Noel, Sanjeev; Saxena, Ankit et al. (2016) Double-Negative ?? T Cells Are Early Responders to AKI and Are Found in Human Kidney. J Am Soc Nephrol 27:1113-23
Noel, Sanjeev; Hamad, Abdel R A; Rabb, Hamid (2015) Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases. Kidney Int 88:1217-1218
Martina, Maria N; Noel, Sanjeev; Saxena, Ankit et al. (2015) Double negative (DN) ?? T cells: misperception and overdue recognition. Immunol Cell Biol 93:305-10
Noel, Sanjeev; Martina, Maria N; Bandapalle, Samatha et al. (2015) T Lymphocyte-Specific Activation of Nrf2 Protects from AKI. J Am Soc Nephrol 26:2989-3000
Dai, Hong; Rahman, Ayesha; Saxena, Ankit et al. (2015) Syndecan-1 identifies and controls the frequency of IL-17-producing naïve natural killer T (NKT17) cells in mice. Eur J Immunol 45:3045-51
Martina, M N; Noel, S; Bandapalle, S et al. (2014) T lymphocytes and acute kidney injury: update. Nephron Clin Pract 127:51-5