Expansion of immunoglobulin autoreactive T-helper cells in multiple myeloma

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2725-2732 ◽  
Author(s):  
Masih Ostad ◽  
Margareta Andersson ◽  
Astrid Gruber ◽  
Anne Sundblad
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Single Cell Analysis ◽  
T Helper ◽  
Cell Reactivity ◽  
Th Cells

Activation and expansion of T helper (Th) cells followed by regulation of activation are essential to the generation of immune responses while limiting concomitant autoreactivity. In order to characterize T cells reactive towards myeloma-derived monoclonal immunoglobulin (mIg), an autologous coculture assay for single-cell analysis of mIg-responding cells was developed. When cultured with dendritic cells loaded with mIg, CD4+ Th cells from patients with progressing multiple myeloma (MM) showed a proliferative MHC class II–dependent response. CD8+ T-cell reactivity and Th1 activation were consistently low or absent, and Th2 and regulatory cytokines were expressed. The presence of such non-Th1 CD4+ T cells in peripheral blood was independent of treatment status, while the frequencies of responding cells varied between patients and reached the same order of magnitude as those measured for tetanus toxoid–specific Th memory cells. Furthermore, investigations of T-cell subpopulations indicated a possible regulatory role on the mIg responsiveness mediated by suppressive CD25highFOXP3+CD4+ T cells. It is proposed from the present results that a predominant in vivo activation of non-Th1 mIg-reactive CD4+ T cells constitute an Ig-dependent autoregulatory mechanism in human MM, with possible tumor growth supporting or permissive effects.

Follicular Lymphoma Tumor Infiltrating T-Helper (Th) Cells Have the Same Intrinsic Polyfunctional Response Potential Upon Stimulation as Do Reactive and Normal Lymph Node Th Cells Despite Having Skewed Differentiation; Implications for Immunotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3119-3119
Author(s):  
Shannon P. Hilchey ◽  
Alexander F. Rosenberg ◽  
Ollivier Hyrien ◽  
Shelley Secor-Socha ◽  
Matthew R. Cochran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Follicular Lymphoma ◽  
Cd4 T Cells ◽  
Th2 Cells ◽  
T Helper ◽  
Th Cells ◽  
Cytokine Profiles ◽  
Th1 And Th2

Abstract Abstract 3119 Tumor infiltrating T-cells tend to be hypo-functional and this loss of function may be due to intrinsic T-cell defects, impaired antigen (Ag) presentation, and/or suppression induced by extrinsic components of the microenvironment, such as regulatory T-cells (Tregs). Each of these potential mechanisms has distinct implications on the potential efficacy of immunotherapy. To determine the functional potential of follicular lymphoma (FL) derived T-cells, we analyzed, by flow cytometry, T helper (Th) subsets and Staphylococcus enterotoxin B (SEB)-induced cytokine profiles of single cell suspensions from FL involved nodes (FL; n=8), reactive lymph nodes (RLN; n=7) and normal lymph nodes (NLN; n=6; obtained during vascular surgery). SEB was used as it directly triggers the T-cell receptor, abrogating the need for Ag presentation, and overcomes Treg mediated suppression. Herein we show that, relative to NLN, FL has decreased proportions of CD4+ T-cells having either a naïve (CD45RA+) or central memory (CD45RA−CCR7+) phenotype but increased proportions of effector memory T-cells (CD45RA−CCR7−). In addition, a higher percentage of pre-stimulation FL CD4+ T-cells show an activated (CD69+) phenotype as compared to that of RLN or NLN. Upon SEB stimulation, the FL CD4+ T-cells, like those from RLN and NLN, show an additional increase in the proportion of CD69+ cells, demonstrating that the FL derived CD4+ T-cells can be activated even further. We also show that upon stimulation with SEB; (a) the proportion of Th1 cells (IL-2+IFN-g+IL-4−) in FL is similar to that seen in RLN or NLN; (b) in contrast, we observe an increased frequency of primed uncommitted precursor Thpp cells (IL-2+IFN-g−IL-4−) in FL compared to that seen in either RLN or NLN; (c) an increased proportion of Th2 cells in FL compared with NLN and; (d) an increase in the proportion of Th17 cells in FL compared to that in RLN. Lastly, the proportions of FL Th cells producing 3 or 4 cytokines simultaneously, or poly-functional CD4+ T-cells, (PFT; PFT-3 producing IL-2, IFN-g and TNF-a or PFT-4 producing IL-2, IFN-g, TNF-a and MIP-1b), after SEB stimulation is similar to that seen in RLN or NLN. These data suggest that although there is skewed Th cell differentiation in FL, as compared to that of RLN or NLN, the intrinsic ability of the FL Th cells to elicit a clinically relevant effector response (both a Th1 and Th2 response) is fully preserved. In addition, the retention of effector function of FL Th cells is further supported by the fact that the proportions of these Th cells that have poly-functional cytokine profiles after SEB stimulation is similar in FL as compared to RLN or NLN. Indeed, poly-functionality of Th cells has been shown to correlate with the elicitation of protective immunity after vaccination for infectious diseases. Finally, the proportion of uncommitted Thpp cells after SEB stimulation is highest in FL. Thpp cells are non-polarized and can still differentiate into either Th1 or Th2 cells. They can also produce several chemokines and thus may play a role in shaping the FL microenvironment by recruiting other immune-effector cells as well as developing into Th1 and Th2 cells. Taken together, our data shows that FL Th cells are fully functional within the parameters of our assays, suggesting that these cells are intrinsically capable of mediating effective anti-tumor immune responses after immunotherapy. Therefore the hypo-functionality of FL T-cells is likely due to extrinsic factors which suppress T-cell function in vivo. Thus the challenge is to develop immunotherapeutic strategies that overcome these tumor associated extrinsic mechanisms, resulting in effective anti-tumor immunity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL

2005 ◽  
Vol 202 (8) ◽  
pp. 1109-1119 ◽  
Author(s):  
Nagendra R. Hegde ◽  
Claire Dunn ◽  
David M. Lewinsohn ◽  
Michael A. Jarvis ◽  
Jay A. Nelson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Glial Cells ◽  
Human Cytomegalovirus ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Host Cells ◽  
Cd4 T Cell

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB—expressed by adenovirus vectors or after HCMV infection—and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells.

Histone Deacetylase Inhibitors Induce Immuno-Dominant Suppression of Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 456-456 ◽  
Author(s):  
Pavan Reddy ◽  
Yoshinobu Maeda ◽  
Raimon Duran-Struuck ◽  
Oleg Krijanovski ◽  
Charles Dinarello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Hdac Inhibitors ◽  
Class Ii ◽  
Wild Type ◽  
Tnf Α

Abstract We and others have recently demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor with anti-neoplastic properties, reduces experimental acute graft-versus-host disease (GVHD). We have now investigated the mechanisms of action of two HDAC inhibitors, SAHA and ITF 2357, on allogeneic immune responses. Bone marrow derived dendritic cells (DCs) were preincubated with the HDAC inhibitors at nanomolar concentrations for 16–18 hours and stimulated with lipopolysaccharide (LPS). Pretreatment of DCs caused a significant reduction in the secretion of TNF-α, IL-12p70 and IL-6 compared to the untreated controls (P< 0.005). Similar effects were seen using human peripheral blood mononuclear cell derived DCs. Pre-treatment of both murine and human DCs also significantly reduced their in vitro stimulation of allogeneic T cells as measured by proliferation and IFN-γ production (P<0.01). We determined the in vivo relevance of these observations utilizing a mouse model where the responses of allogeneic donor bm12 T cells depended on the function of injected host B6 DCs would stimulate. Recipient Class-II −/− B6 (H-2b) received 11 Gy on day -1 and were injected with 4–5 x 106 wild type B6 DCs treated with SAHA or with media on days -1 and 0 and then transplanted with 2 x 106 T cells and 5 x 106 TCDBM cells from either syngeneic B6 or allogeneic bm12 donors. SAHA treatment of DCs significantly reduced expansion of allogeneic donor CD4+ T cells on day +7 after BMT compared to controls (P<0.05). SAHA treatment induced a similarly significant reduction in the expansion of CD8+ cells in Class I disparate [bm1→β2M−/−] model. In vitro, SAHA treatment significantly suppressed the expression of CD40 and CD80 but did not alter MHC class II expression. Surprisingly, when mixed with normal DCs at 1:1 ratio, SAHA treated DCs dominantly suppressed allogeneic T cell responses. The regulation of T cell proliferation was not reversible by addition of IL-12, TNF-α, IL-18, anti-IL-10 or anti-TGFβ, either alone or in combination. Suppression of allogeneic responses was contact dependent in trans-well experiments. To address whether the regulation of SAHA treated DCs required contact with T cells, we devised a three cell experiment where SAHA treated DCs lacked the capacity to present antigens to T cells. DCs from B6 MHC Class II deficient (H-2b) were treated with SAHA and co-cultured with wild type B6 (H-2b) DCs along with purified allogeneic BALB/c (H-2d) CD4+ T cells in an MLR. Allogeneic CD4+ T cells proliferated well, demonstrating the regulation to be dependent on contact between SAHA treated DCs and T cells. To address the in vivo relevance of this suppression, we utilized a well characterized [BALB/c →B6] mouse model of acute GVHD. Recipient B6 animals received 11Gy on day -1 and were injected with of 5 million host type SAHA treated or control DCs on days −1, 0, and +2. Mice were transplanted on day 0 with 2 x 106 T cells and 5 x 106 BM from either syngeneic B6 or allogeneic BALB/c donors. Injection of SAHA treated DCs resulted in significantly better survival (60% vs. 10%, P < 0.01) and significantly reduced serum levels of TNF-α, donor T cell expansion and histopathology of GVHD on day +7 after BMT compared to the controls. We conclue that HDAC inhibitors are novel immunomodulators that regulate DC function and might represent a novel strategy to prevent GVHD.

Critical Role of Neutrophils in Determining Antigen-Specific CD4+ T-Cell Tolerance In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3294-3294
Author(s):  
Fengdong Cheng ◽  
Pedro Horna ◽  
Hongwei Wang ◽  
Ildefonso Suarez ◽  
Xianhong Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
High Dose ◽  
Wild Type ◽  
Cognate Antigen ◽  
Induced Tolerance

Abstract In previous studies we have shown that Signal Transducer and Activator of Transcription 3 (STAT3) negatively regulates inflammatory responses in myeloid cells and plays a central role in determining immune activation versus immune tolerance of antigen-specific CD4+ T-cells. Indeed, in Stat3 knock out mice (LysMcre/Stat3flox/−) in which macrophages and neutrophils are devoid of Stat3, we found that in response to a tolerogenic stimulus (high dose peptide-induced tolerance or tumor-induced tolerance models) adoptively transferred antigen-specific CD4+ T-cells are not tolerized but instead are effectively primed as determined by their production of IL-2 and IFN-gamma in response to cognate antigen. Such an observation led us to investigate which cell population(s) is required for the priming effect observed in Stat3 KO mice. First, we used anti-Gr-1 antibody to deplete neutrophils in wild type BALB/c mice as well as Stat3 KO mice. Briefly, half the mice in each group were treated with 0.5mg of the antibody given i.p. every 3 days from day-3 until day +15. On day zero, all the mice were adoptively transferred with 2.5 x 106 naïve transgenic CD4+ T-cells specific for a MHC class II restricted epitope of hemaglutinin (HA). On day +2, animals received high dose of HA peptide (275 mcg) given i.v. Mice were sacrificed on day +15 and clonotypic T-cells were re-isolated from their spleens to assess their functional status following their in vivo exposure to this tolerogenic stimuli. A striking difference was observed in T-cells isolated from Stat3 KO mice with an intact neutrophil compartment (non-depleted) versus T-cells from anti-Gr-1 treated LysMcreStat3flox/− mice. Unlike T-cells from the former group in which priming was the functional outcome, clonotypic T-cells from LysMcreStat3flox/− mice depleted of neutrophils, were found to be anergic. Therefore, the T-cell priming effect observed in LysMcreStat3flox/− mice requires an intact neutrophil compartment given that in the absence of this population, tolerance not priming was the functional T-cell outcome. To gain insight into the potential mechanism(s) by which neutrophils devoid of Stat3 influence T-cell responses, we next analyzed the phenotypic and functional properties of neutrophils isolated from Stat3 KO mice and wild type controls. First, the lack of expression of MHC class II molecules by neutrophils from WT and KO mice made unlikely the possibility that neutrophils devoid of Stat3 could directly present antigen to CD4+ T-cells. However, when neutrophils from Stat3−/− conditional mice were added to macrophages monolayers in vitro, the antigen-presenting capabilities of macrophages was significantly enhanced as determined by the increased production of IL-2 and IFN-gamma by antigen-specific T-cells encountering cognate antigen in these APCs. Furthermore, macrophages cultured in vitro with neutrophils from Stat3−/− conditional mice were able to restore the responsiveness of tolerant CD4+ T-cells. This effect that was not observed when tolerized T-cells encountered cognate antigen in macrophages incubated with neutrophils from wild type mice. Trans-well experiments demonstrated that the regulatory effect of neutrophils upon APCs function required cell-cell contact. Taken together, we have unveiled a previously unrecognized role of neutrophils in determining the functional outcome of antigen-specific T-cell responses, effect that is dependent upon the interaction of neutrophils with antigen-presenting cells.

scholarly journals In Vitro Generation of Multi-Epitope Specific CD4+ T Helper Cells for Adoptive Immunotherapy of Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1890-1890
Author(s):  
Pawel Muranski ◽  
Scott Stegemann ◽  
Greg Whitehill ◽  
A John Barrett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Cultures ◽  
Adoptive Immunotherapy ◽  
Tumor Antigen ◽  
Cd4 T Cells ◽  
Class Ii ◽  
T Helper ◽  
Th Cells

Abstract Introduction: Acute myeloid leukemia (AML) and other hematological malignancies that constitutively express MHC class II molecules represent the ideal target for leukemia-specific CD4+ T helper (Th) cells. CD4+ Th cells are central to the functioning of the immune system. They regulate adaptive immunity against infections and drive pathogenic responses in many autoimmune diseases. Our preclinical studies indicate that adoptively transferred antigen specific Th cells efficiently eradicate even advanced tumors in mice, showing functional advantage over their better characterized classical CD8+ cytotoxic counterparts. Unfortunately, the production of human class II-restricted Th cells is complex and challenging. Consequently, the clinical activity of tumor-specific Th cells has not been systematically evaluated and very little is known about their therapeutic potential in humans. Striking evidence of their enormous power comes from some anecdotal clinical reports of complete regression of metastatic cancers upon transfer of antigen-specific Th cells. Methods and Results: We investigated a reliable GMP-compatible method for in vitro expansion of antigen-specific CD4+ T cells targeting common leukemia associated antigens (LAAs) Willm's Tumor antigen 1 (WT1) and Preferentially Expressed Antigen in Melanoma (PRAME) for future adoptive immunotherapy in the setting of allogeneic stem cell transplantation (SCT). We hypothesized that the naïve CD4+ T cell compartment, rather than the bulk Th cell population could be a superior source for generating a tumor antigen specific cell product. To test this hypothesis bulk and naïve CD4+ T cells were isolated from the peripheral blood of normal donors by magnetic bead separation. Purified T cells were stimulated in vitro with autologous dendritic cells (DCs) pulsed with overlapping 15 amino-acid long peptide (pepmixes) spanning the length of both proteins. Two rounds of stimulation were performed in presence of IL-7, IL-15 and later +/- addition of IL-1, IL-6 and IL-23. IL-2 in low concentration was supplemented during the second round of stimulation. At the end of the second expansion the cells were tested for reactivity by intracellular cytokine production using flow cytometry (FACS) upon stimulation with cognate LAAs or irrelevant control pepmixes. In T cell cultures derived from naïve CD4+ T cells we observed robust induction of PRAME reactivity from majority of tested normal donors, while reactivity against WT1 was donor dependent. The frequency of LAAs in bulk CD4+ T cells was significantly lower in all cases, supporting the notion that pre-exiting memory Th cells have a competitive advantage over the LAA-specific precursor. T cell cultures supplemented with inflammatory cytokines demonstrated further enhancement of antigenic reactivity. Next we tested if LAA pepmix -stimulated T cells can recognize tumor targets. Naïve-derived PRAME and WT1 Th cells generated from normal SCT sibling donors produced IFN-γ, IL-2 and TNF-α upon exposure to fully HLA-matched AML blasts while no reactivity was seen in control CMV pp65-specific Th cells from the same donors. This observation suggests that LAA-specific CD4+ T cells induced with pepmixes have the ability to recognize physiologically-relevant tumor antigens. Conclusions: Here we report the feasibility of generating naïve-derived anti-leukemia CD4+ T cells from majority of normal donors. Removal of competing memory Th cells unmasks the LAA-specific reactivity, thus improving the reliability of the process. Importantly, these Th cells demonstrate highly-specific recognition of the tumor epitopes naturally processed by HLA-matched leukemic blasts, establishing the foundation for a future adoptive immunotherapy clinical trial in patients with hematological malignancy. Disclosures No relevant conflicts of interest to declare.

scholarly journals MHC control of CD4+ T cell subset activation.

1989 ◽  
Vol 170 (6) ◽  
pp. 2135-2140 ◽  
Author(s):  
J S Murray ◽  
J Madri ◽  
J Tite ◽  
S R Carding ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Selective Activation ◽  
Ifn Gamma

The present results demonstrate that CD4+ T cells activated in the primary in vivo response to antigen produce distinct patterns of cytokines depending upon the MHC class II haplotype of the responding mice. I-As mice were found to selectively activate IL-2/IFN-gamma-producing CD4+ T cells, whereas I-Ab mice exhibited selective activation of IL-4-producing CD4+ T cells in response to collagen IV. The effector response phenotype was found to correlate with the cytokine phenotype of CD4+ T cells activated in vivo; IL-2/IFN-gamma-producing cells giving rise to proliferative (cell-mediated) responses, IL-4-producing cells leading to secondary IgG (humoral) responses. Together the data support the notion that the outcome of a given immune response (e.g., protection vs. onset, tolerance vs. autoimmunity) may be determined in part by the type of CD4+ T cells initially activated by antigen. Moreover, the present experiments demonstrate for the first time that polymorphism in class II MHC can determine such selective activation of different cytokine-producing CD4+ T cell phenotypes.

scholarly journals The MRC OX-22- CD4+ T cells that help B cells in secondary immune responses derive from naive precursors with the MRC OX-22+ CD4+ phenotype.

1989 ◽  
Vol 169 (3) ◽  
pp. 653-662 ◽  
Author(s):  
F Powrie ◽  
D Mason
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cd4 T Cells ◽  
Antibody Responses ◽  
Cell Reactivity ◽  
Helper Activity ◽  
T Cell Reactivity ◽  
Paper Address

CD4+ T cells in the rat can be divided into two nonoverlapping subsets by their reactivity with the mAb MRC OX-22, which binds some of the high molecular weight forms of the CD45 antigen. The lineage relationship between subsets of CD4+ T cells expression different forms of CD45 has been a controversial issue for some time. Experiments described in this paper address this question using in vivo assays of T cell reactivity. Analysis of primary antibody responses in vivo show that it is MRC OX-22+ CD4+ T cells that are active in these assays, whereas antigen-primed T cells that provide helper activity for secondary antibody responses in vivo have the MRC OX-22- CD4+ phenotype. It is demonstrated that these memory T cells derive from MRC OX-22+ CD4+ T cell precursors and not from a putative separate lineage. It is concluded that with respect to the provision of help for B cells, MRC OX-22+ CD4+ T cells are precursors of memory cells with the phenotype MRC OX-22- CD4+.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

Abstract P285: Hydralazine Attenuates the Development of Hypertension in the Female Dahl Salt-sensitive Rat in a T Cell-independent Manner

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Amrita V Pai ◽  
Crystal A West ◽  
Aline Souza ◽  
Parnika S Kadam ◽  
Emma J Pollner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rat Kidney ◽  
T Helper ◽  
Independent Manner ◽  
Th Cells ◽  
Time Treatment ◽  
Salt Sensitive Hypertension ◽  
Cell Profile

Introduction: Several studies in Dahl salt-sensitive ( DS ) rats suggest that T cells play a role in salt-sensitive hypertension. To further investigate the role of T cells, we compared T cell profiles in hypertensive DS and normotensive Dahl salt-resistant ( DR ) rats as well as in DS rats treated with hydralazine ( HYD ) to attenuate the development of hypertension. Methods: Mean arterial pressure ( MAP ) was measured by telemetry in DS rats (n=13) from 1 to 4.5 months ( mo ) of age. At 1.5 mo, all of the DR (n=8) and half of the DS rats were treated with vehicle (VEH, n=7). The other half of the DS rats (n=6) received HYD (25 mg/kg/day) in the drinking water. At 4.5 mo, renal T helper ( Th ) and cytotoxic ( Tc ) cells were assessed by multicolor flow cytometry. Results: In the DS kidney, the frequency of CD4 + Th cells [(%): DS-VEH, 76±1.2* vs. DR-VEH, 55±0.7; *p<0.0001; n=7-8/group] was higher while the frequency of CD8 + Tc cells [(%): DS-VEH, 14±1.2* vs. DR-VEH, 35±1; *p<0.0001; n=7-8/group] was lower compared to DR rats. 10 weeks of HYD treatment attenuated the age-associated increase in MAP observed in DS rats [p<0.0001, Two-Way ANOVA (time, treatment); MAP (mmHg): DS-VEH, 157±4 vs. DS-HYD, 133±3; *p<0.0004; n=6-7/group]. HYD had no effect on the frequency of CD4 + [(%):77±1.5] or CD8 + [(%):15.5±0.9] T cells in the kidney of DS rats [(CD4 + ): DS-VEH vs. DS-HYD, p=0.83; (CD8 + ): DS-VEH vs. DS-HYD, p=0.5; n=7-8/group]. In summary, the ratio of Th (CD4 + ) to Tc (CD8 + ) cells is higher in the kidney of DS compared to DR rats and HYD had no effect on the T cell profile in the DS rat kidney under conditions in which the MAP was attenuated by 20 mm Hg. Conclusions: These findings indicate the DS rat has more active Th cells in the kidney compared to the DR rat. Our study also suggests that vasodilators can attenuate the development of hypertension in the DS rat in a Th- and Tc-independent manner.

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