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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: S218S225.
Freely available at
jasn.asnjournals.org/content/17/12_suppl_3/S218.full.pdf
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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
p < 0.05
p < 0.001
p < 0.05
p < 0.001
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-KinaseMediated 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-KinaseMediated 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/nature
11984.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/nature
11984.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 IIInduced 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
Annet Kirabo
Wei Chen
Salim Thabet
Hana Itani
Liang Xiao
Dan Trott
Jing Wu
Jing Wu
Meena Madhur
Jens Titze
Mohamed Saleh
Sergey Dikalov
Sean Davies
Ken Bernstein
(Cedars Sinai)
Connie Weyand
Jorg Goronzy
Jack Roberts
Tom Guzik
(Cracow)