Abstract 178: Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in Experimental Autoimmune Mocarditis

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Pablo Nakagawa ◽  
Pablo Nakagawa
Keyword(s):  
T Cell ◽  
Adhesion Molecules ◽  
Inflammatory Cytokines ◽  
Cell Adhesion Molecules ◽  
Cardiac Injury ◽  
Cell Mediated Immunity ◽  
T Helper ◽  
Helper Type ◽  
Experimental Autoimmune ◽  
Pro Inflammatory Cytokines

Background: Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a naturally occurring tetrapeptide, prevents autoimmune cardiac dysfunction and remodeling. The mechanism by which this occurs remains unknown. Experimental autoimmune myocarditis (EAM), a T cell-mediated autoimmune disease, is a model of autoimmune cardiac injury. Cytokines and adhesion molecules are necessary for the development of EAM. We hypothesized that Ac-SDKP prevents autoimmune cardiac injury by reducing T cell response, pro-inflammatory cytokines and adhesion molecules. Methods and results: EAM was induced by immunization of rats with porcine cardiac myosin, followed by s.c. infusion of vehicle or Ac-SDKP (800 μg.kg-1.d-1) via osmotic minipumps. By 3 weeks post-immunization, we evaluated cell-mediated immunity by delayed-type hypersensitivity, myocardial T helper infiltration by immunohistochemistry and both cytokines and adhesion molecules were measured with a proteomic array kit. Ac-SDKP prevented increases in 1) Delayed-type sensitivity (EAM, 0.35±0.06 vs EAM + Ac-SDKP, 0.16±0.01** mm), 2) infiltration by T helper cells (148±20 vs 97±17*** CD4 cells/mm2), 3) pro-inflammatory cytokines [Tumor necrosis factor-α (0.98±0.20 vs 0.17±0.03** A.U.); Interleukin (IL)-1β (13.7±2.9 vs 0.29±0.07*** A.U.); IP-10, a T helper type 1 chemokine (1.54±0.23 vs 0.30±0.08*); IL-17, a T helper type 17 cytokine (1.9±0.3 vs 0.8±0.3* A.U.)] and 4) Cell adhesion molecules [L-selectin (42.4±4.8 vs 9.1±1.9***) and Intercellular adhesion molecule 1 (54.1±3.1 vs 19.1±2.8***)]. Conclusion: Prevention of autoimmune cardiac injury by Ac-SDKP is correlated by decreased cell-mediated immunity. The protective effects of Ac-SDKP are likely mediated by reduction of T cell infiltration, pro-inflammatory cytokines and cell adhesion molecules. *p<0.05, **p<0.005, and ***p<0.001 EAM vs EAM + Ac-SDKP

Constitutive Expression of CD40L by CAR-Modified Tumor Targeted T Cells Enhances Anti-Tumor Efficacy Both in Vitro and in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4120-4120 ◽  
Author(s):  
Kevin J. Curran ◽  
Beatrijs Seinstra ◽  
Yan Nikhamin ◽  
Raymond Yeh ◽  
Yelena Usachenko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Adhesion Molecules ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Cd40 Ligand ◽  
Tumor Cell Lines ◽  
Pro Inflammatory Cytokines

Abstract Abstract 4120 T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). Recent reports have demonstrated the effectiveness of CAR modified T cells in patients with relapsed or refractory malignancies. However, CAR modified T cells have yet to demonstrate the ability to recruit an endogenous anti-tumor response which would greatly enhance their therapeutic benefit. To overcome these limitations we have developed a bi-cistronic gamma-retroviral vector allowing for constitutive co-expression of a CD19-specific CAR (19–28z) and human CD40 ligand (CD40L; CD154). The CD40 ligand/CD40 system has been demonstrated to activate dendritic cells (DCs) and alter the phenotype of B cells (upregulation of co-stimulatory and adhesion molecules and secretion of pro-inflammatory cytokines) with subsequent stimulation of CD8+ T cell activation and proliferation. We now demonstrate T cells genetically modified to constitutively express CD40L undergo enhanced proliferation and up-regulated secretion of pro-inflammatory cytokines including GM-CSF and INF-g. Furthermore, T cells modified to constitutively express CD40L, upon co-culture, will alter the phenotype of CD40+ B cell tumor cell lines by enhancing the expression co-stimulatory molecules (CD80/CD86), adhesion molecules (CD54/CD58/CD70) and death receptors (CD95; Fas). These findings were similarly evident in primary patient tumor samples (e.g. CLL cells) when co-cultured with autologous T cells modified to constitutively express CD40L. We further demonstrate maturation of monocyte derived DCs with subsequent secretion of IL-12 following co-culture with autologous T cells modified to constitutively express CD40L. T cells transduced with the bi-cistronic 19–28z/CD40L vector showed enhanced in vitro cytotoxicity against a panel of CD19+ tumor cell lines. Furthermore, infusion of 19–28z/CD40L modified T cells enhances the survival of CD19+ tumor bearing immunodeficient mice (SCID/Beige) when compared to mice treated with T cells modified to express the anti-CD19 19–28z CAR alone. We conclude that further genetic modification of CAR targeted T cells to constitutively express the co-stimulatory CD40L may enhance the anti-tumor efficacy of this adoptive T cell therapy. Our data suggests this enhanced T cell efficacy may be due to both autocrine and paracrine mediated mechanisms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

2002 ◽  
Vol 196 (5) ◽  
pp. 619-628 ◽  
Author(s):  
Tomohide Tatsumi ◽  
Lisa S. Kierstead ◽  
Elena Ranieri ◽  
Loreto Gesualdo ◽  
Francesco P. Schena ◽  
...  
Keyword(s):  
T Cell ◽  
Renal Cell ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Current Evidence ◽  
Cell Mediated Immunity ◽  
T Helper ◽  
Cell Responses ◽  
Helper Type

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit.

scholarly journals Potential Antiinflammatory Role of Insulin via the Preferential Polarization of Effector T Cells toward a T Helper 2 Phenotype

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 346-353 ◽  
Author(s):  
Alexander Viardot ◽  
Shane T. Grey ◽  
Fabienne Mackay ◽  
Donald Chisholm
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Insulin Receptor ◽  
T Cell Differentiation ◽  
Receptor Expression ◽  
T Helper ◽  
Type Response ◽  
Helper Type

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-γ to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.

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