Immune Control of the Cardiovascular System David G. Harrison, M.D., Vanderbilt University School of Medicine

Early Studies of Immunity and Hypertension 1. White FN, Grollman A. Autoimmune factors associated with infarction of the kidney. Nephron. 1964;204:93-102 2. Okuda T, Grollman A. Passive transfer of autoimmune induced hypertension in the rat by lymph node cells. Tex Rep Biol Med. 1967;25:257-264 3. Svendsen UG. The role of thymus for the development and prognosis of hypertension and hypertensive vascular disease in mice following renal infarction. Acta Pathol Microbiol Scand A. 1976;84:235-243 4. Svendsen UG. Evidence for an initial, thymus independent and a chronic, thymus dependent phase of DOCA and salt hypertension in mice. Acta Pathol Microbiol Scand A. 1976;84:523-528 5. Olsen F. Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients. Acta Pathol Microbiol Scand C. 1980;88:1-5  

Reduction of Renal Injury by MMF in 5/6 Nephrectomy Model Fig. 4, A-F. From Tapia et al. Kidney Int. 2003, 63:994-1002. Freely available at www.nature.com/ki/journal/v63/n3/full/4493520a.html

Hypertension Induced by Aortic Coarctation Above the Renal Arteries Is Associated With Immune Cell Infiltration of the Kidneys Fig. 3. From Rodriguez-Iturbe et al. Am J Hypertens 2005; 18:1449–1456. Available at http://ajh.oxfordjournals.org/content/18/11/1449.full

Mycophenolate Mofetil Treatment Improves Hypertension in Patients with Psoriasis and Rheumatoid Arthritis Fig. 1, A & B. From Herrera et al. J Am Soc Nephrol 2006; 17: S218-S225. Freely available at jasn.asnjournals.org/content/17/12_suppl_3/S218.full.pdf

Mycophenolate Mofetil Treatment Improves Hypertension in Patients with Psoriasis and Rheumatoid Arthritis Data from Table 3. From Herrera et al. J Am Soc Nephrol 2006; 17: S218-S225. Freely available at jasn.asnjournals.org/content/17/12_suppl_3/S218.full.pdf

Kidney in Malignant Hypertension Figure from famous Pathology textbook – current edition, showing normal kidney vs. kidney in malignant hypertension

T Cells and Hypertension RAG1-/- mice, lacking T and B cells, exhibit blunted hypertension to Angiotensin II, DOCA-salt and norepinephrine Fig. 1, A-C. From Guzik et al. J Exp Med 2007; 204:2449-2460. Freely available at jem.rupress.org/content/204/10/2449.full

Effect of Lymphocyte Adoptive Transfer on Hypertension in Rag-/- Mice Fig. 4B (top 2 lines and bottom line). From Guzik et al. J Exp Med 2007; 204:2449-2460. Freely available at jem.rupress.org/content/204/10/2449.full Fig. 4F. From Marvar et al. Circ Res. 2010; 107: 263-270. Freely available at circres.ahajournals.org/content/107/2/263.full

Lymphocyte Responses Exacerbate Angiotensin II-Dependent Hypertension Fig. 1, B and C. From Crowley et al., Am J Physiol Regul Integr Comp Physiol 298: R1089–R1097, 2010. Freely available at ajpregu.physiology.org/content/298/4/R1089.full (Reprinted with permission)

Genetic Mutation of Recombination Activating Gene 1 in Dahl Salt-sensitive Rats Attenuates Hypertension and Renal Damage Fig. 3. From Mattson et al. Am J Physiol Regul Integr Comp Physiol 2013; 304: R407–R414. Available at http://ajpregu.physiology.org/content/304/6/R407.full Reprinted with permission.

Genetic Mutation of Recombination Activating Gene 1 in Dahl Salt-sensitive Rats Attenuates Hypertension and Renal Damage Figs. 5 and 6. From Mattson et al. Am J Physiol Regul Integr Comp Physiol 2013; 304: R407–R414. Available at http://ajpregu.physiology.org/content/304/6/R407.full Reprinted with permission.

Cytokines Mediating Hypertension and Vascular Dysfunction Periadvential Fat T cells Cytokines

Cytokines Implicated in Hypertension Tumor necrosis factor a Interleukin 17 Interferon g Interleukin 6 Tissue growth factor b Interleukin 10

IL17 is Required for the Maintenance of Ang II-Induced Hypertension Fig. 2, A & C (showing systolic BP only). From Madhur et al. Hypertension 2010; 55: 500-507. Freely available at hyper.ahajournals.org/content/55/2/500.full

Ang II Increases T Cell IL17 Production and Circulating TH17 Cells Fig. 1. From Madhur et al. Hypertension 2010; 55: 500-507. Freely available at hyper.ahajournals.org/content/55/2/500.full

IL-17 Contributes to Vascular Superoxide Production in Ang II-Induced Hypertension Fig. 4, D & E. From Madhur et al. Hypertension 2010; 55: 500-507. Freely available at hyper.ahajournals.org/content/55/2/500.full

Reduced Inflammatory Response in the Vasculature of IL17-/- Mice in Response to Angiotensin II Fig. 5, B & C. From Madhur et al. Hypertension 2010; 55: 500-507. Freely available at hyper.ahajournals.org/content/55/2/500.full

IL-17 Levels in Normotensive and Hypertensive Patients with Type II DM Table 1. From Madhur et al. Hypertension 2010; 55: 500-507. Freely available at hyper.ahajournals.org/content/55/2/500.full

Interleukin-17 Causes Rho-Kinase-Mediated Endothelial Dysfunction and Hypertension Figs. 1A and 3, A & B. From: Nguyen et al. Cardiovasc Res 2013; 97: 696–704. Available at cardiovascres.oxfordjournals.org/content/97/4/696.full

Interleukin-17 Causes Rho-Kinase-Mediated Endothelial Dysfunction and Hypertension Figure 4B. From Nguyen et al. Cardiovasc Res 2013; 97: 696–704. Available at cardiovascres.oxfordjournals.org/content/97/4/696.full

Induction of Pathogenic TH17 Cells by Inducible Salt-Sensing Kinase SGK1 Figs. 1b, 2c & 2d (right-side). From Wu et al. Nature 2013; 496:513-517. Available at www.nature.com/nature/journal/v496/n7446/full/nature11984.html

Induction of Pathogenic TH17 Cells by Inducible Salt-Sensing Kinase SGK1 Fig. 4a. From Wu et al. Nature 2013; 496:513-517. Available at www.nature.com/nature/journal/v496/n7446/full/nature11984.html

Renal Hypertonicity and IL-17 Levels in Angiotensin II-Induced Hypertension Figure not available; unpublished data.

Flow Cytometry Detection of Tc17 Cells in the Kidney Figure not available; unpublished data.

Figure not available; unpublished data.

Tc17 Cells Mediate Renal Microvascular Remodeling in Hypertension Figure not available; unpublished data.

Role of Tc17 Cells in Renal Sodium and Volume Excretion Figure not available; unpublished data.

Classic Pathway for T Cell Activation – Role of Co-Stimulation Figure not available; unpublished data.

Effect of CTLA4IG on Angiotensin II-Induced Hypertension Fig. 1, C & D. From Vinh et al. Circulation 2010; 122: 2529–2537. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3064430

Effect of CTLA4-Ig on Established DOCA-Salt Hypertension Fig. 8B. Vinh et al. Circulation 2010; 122: 2529–2537. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3064430/

Effect of CTLA4-Ig on Established DOCA-Salt Hypertension Fig. 5. Vinh et al. Circulation 2010; 122: 2529–2537. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3064430/

Collaborators and Contributors Harrison Lab Madhur Lab Stanford Connie Weyand Jorg Goronzy Annet Kirabo Wei Chen Salim Thabet Hana Itani Liang Xiao Dan Trott Jing Wu Meena Madhur Jens Titze Mohamed Saleh Sergey Dikalov Sean Davies Ken Bernstein (Cedars Sinai) Jack Roberts Tom Guzik (Cracow) Jing Wu