• 1.

    Katayama M, McAnulty JF. Renal transplantation in cats: techniques, complications, and immunosupression. Compend Contin Educ Pract Vet 2002; 24:874882.

    • Search Google Scholar
    • Export Citation
  • 2.

    Katayama M, McAnulty. Renal transplantation in cats: patient selection and preoperative management. Compend Contin Educ Pract Vet 2002; 24:868872.

    • Search Google Scholar
    • Export Citation
  • 3.

    Bernsteen L, Gregory CR, Kyles AE, et al. Renal transplantation in cats. Clin Tech Small Anim Pract 2000; 15:4045.

  • 4.

    Gregory CR. Renal transplantation in cats. Compend Contin Educ Pract Vet 1993; 15:13251338.

  • 5.

    Gregory CR. Renal transplantation. In: Bojrab MJ, ed. Current techniques in small animal surgery. 4th ed. Baltimore: Williams & Wilkins, 1998;434.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kadar E, Sykes JE, Kass PH, et al. Evaluation of the prevalence of infections in cats after renal transplantation: 169 cases (1987–2003). J Am Vet Med Assoc 2005; 227:948953.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Bernsteen L, Gregory CR, Aronson LR, et al. Acute toxoplasmosis following renal transplantation in three cats and a dog. J Am Vet Med Assoc 1999; 215:11231126.

    • Search Google Scholar
    • Export Citation
  • 8.

    Nordquist BC, Aronson LR. Pyogranulomatous cystitis associated with Toxoplasma gondii infection in a cat after renal transplantation. J Am Vet Med Assoc 2008; 232:10101012.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Griffin AG, Newton AL, Aronson LR, et al. Disseminated Mycobacterium avium complex infection following renal transplantation in a cat. J Am Vet Med Assoc 2003; 222:10971101.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Wooldridge J, Gregory CR, Mathews KG, et al. The prevalence of malignant neoplasia in feline renal transplant recipients. Vet Surg 2002; 31:9497.

  • 11.

    Schmiedt CW, Grimes JA, Holzman G, et al. Incidence and risk factors for development of malignant neoplasia after feline renal transplantation and cyclosporine-based immunosuppression. Vet Comp Oncol 2009; 7:4553.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Mathews KG, Gregory CR. Renal transplants in cats: 66 cases (1987–1996). J Am Vet Med Assoc 1997; 211:14321436.

  • 13.

    Schmiedt CW, Holzman G, Schwarz T, et al. Survival, complications and analysis of risk factors after renal transplantation in cats. Vet Surg 2008; 37:683695.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kyles AE, Gregory CR, Griffey SM, et al. Evaluation of the clinical and histological features of renal allograft rejection in cats. Vet Surg 2002; 31:4958.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Amirzargar A, Lessanpezeshki M, Fathi A, et al. Th1/Th2 cytokine analysis in Iranian renal transplant recipients. Transplant Proc 2005; 37:29852987.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Saalmuller A. New understanding of immunological mechanisms. Vet Microbiol 2006; 117:3238.

  • 17.

    Rostaing L, Puyoo O, Tkaczuk J, et al. Differences in type 1 and type 2 intracytoplasmic cytokines, detected by flow cytometry, according to immunosuprression (cyclosporine A vs. tacrolimus) in stable renal allograft recipients. Clin Transplant 1999; 13:400409.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Mosmann TR, Fowell DJ. The Th1/Th2 paradigm in infections. In: Kaufman SHE, Sher A, Ahmed R, eds. Immunology of infectious diseases. Washington, DC: ASM Press, 2002;163174.

    • Search Google Scholar
    • Export Citation
  • 19.

    Andre S, Tough DF, Lacroix-Desmazes S, et al. Surveillance of antigen presenting cells by CD4+CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. Am J Pathol 2009; 174:15751587.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Hashimoto M, Sakaguchi S. Contribution of Th-1, Th-2, TH-17 or regulatory T cells to connective tissue diseases [in Japanese]. Nippon Rinsho 2009; 67:482486.

    • Search Google Scholar
    • Export Citation
  • 21.

    Miyara M, Wing K, Sakaguchi S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T cell activation and expansion. J Allergy Clin Immunol 2009; 123:749755.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Turka LA. Normal immune responses. In: Norman DJ, Suki WN, eds. Primer on transplantation. Thorofare, NJ: American Society of Transplant Physicians, 1998;720.

    • Search Google Scholar
    • Export Citation
  • 23.

    Basak U, Mitra DK, Panigrahi A, et al. Clinical relevance of monitoring cytokine production following living donor renal transplantation. Transplant Proc 2003; 35:404406.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Poole KL, Gibbs PJ, Evans PR, et al. Influence of patient and donor cytokine genotypes on renal allograft rejection: evidence from a single centre study. Transplant Immunol 2001; 8:259265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Li L, Yuhai Z. The relationship between cytokines in MLC supernatants and acute rejection after renal transplantation. Transplant Proc 2000; 32:25312534.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Divate SA. Acute renal allograft rejection: progress in understanding cellular and molecular mechanisms. J Postgrad Med 2000; 46:293296.

    • Search Google Scholar
    • Export Citation
  • 27.

    McLean AG, Hughes D, Welsh KI, et al. Patterns of graft infiltration and cytokine gene expression during the first 10 days of kidney transplantation. Clin Transplant 1997; 63:374380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Sadeghi MI, Daniel V, Weimer R, et al. Differential early post-transplant cytokine responses in living and cadaver donor renal allografts. Transplantation 2003; 75:13511355.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Gibbs PJ, Sadek SA, Cameron C, et al. Immunomonitoring of renal transplant recipients in the early posttransplant period by analysis of cytokine gene expression in peripheral blood mono-nuclear cells. Transplant Proc 2001; 33:32853286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970; 169:10421049.

  • 31.

    Najafian N, Sayegh MH. CTLA4-Ig: a novel immunosuppressive agent. Exp Opin Invest Drugs 2000; 9:21472157.

  • 32.

    Schaub M, Stadlbauer THW, Chandraker A, et al. Comparative strategies to induce long term graft acceptance in fully allogeneic renal versus cardiac allograft models by CD28-B7 T cell costimulatory blockade: role of thymus and spleen. J Am Soc Nephrol 1998; 9:891898.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Kirk AD, Harlan DM, Armstrong NN, et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94:87898794.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Kurlberg G, Haglind E, Schon K, et al. Blockade of the B7-CD28 pathway by ctla4-Ig counteracts rejection and prolongs survival in small bowel transplantation. Scand J Immunol 2000; 51:224230.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Turka LA, Linsley PS, Lin H, et al. T cell activation by CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci USA 1992; 89:1110211105.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Sayegh MH, Zheng XG, Magee C, et al. Donor antigen is necessary for the prevention of chronic rejection in CTLA4-Ig treated murine cardiac allograft recipients. Transplantation 1997; 64:16461650.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Russell ME, Hancock WW, Akalin E, et al. Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4-Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. J Clin Invest 1996; 97:833838.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Azuman H, Chandraker A, Nadeau K, et al. Blockade of T cell costimulation prevents development of experimental chronic renal allograft rejection. Proc Natl Acad Sci U S A 1996; 93:1243912444.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lin H, Bollong SF, Linsley PS, et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4-Ig plus donor specific transfusions. J Exp Med 1993; 175:18011806.

    • Search Google Scholar
    • Export Citation
  • 40.

    Chandraker A, Azuma H, Nadeau K, et al. Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection. J Clin Invest 1998; 101:23092318.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Akalin E, Chandraker A, Russell ME, et al. CD28-B7 T cell costimulatory blockade by CTLA4-Ig in the rat renal allograft model. Transplantation 1996; 62:19421945.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993; 11:191212.

  • 43.

    Aronson LR, Drobatz KJ, Hunter CA, et al. Effects of CD28 blockade on subsets of naïve T cells in cats. Am J Vet Res 2005; 66:483492.

  • 44.

    Boyum A. A one stage procedure for isolation of granulocytes and lymphocytes from human blood. General sedimentation properties of white blood cells in a 1g gravity field. Scand J Clin Lab Invest Suppl 1968; S97:5176.

    • Search Google Scholar
    • Export Citation
  • 45.

    Gregory CR, Taylor NJ, Willits NH, et al. Response to isoantigens and mitogens in the cat: effects of cyclosporin A. Am J Vet Res 1987; 48:126130.

    • Search Google Scholar
    • Export Citation
  • 46.

    Haczku A, Alexander A, Brown P, et al. the effect of dexamethasone, cyclosporine and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 1994; 93:510519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Wells AD, Gudmundsdottir H, Turka LA. Following the fate of individual T cells throughout activation and clonal expansion. Signals from T cell receptor and CD28 differentially regulate the induction and duration of a proliferative response. J Clin Invest 1997; 100:31733183.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Walker C, Malik R, Canfield PJ. Analysis of leucocytes and lymphocyte subsets in cats with naturally-occurring cryptococcosis but differing feline immunodeficiency virus status. Aust Vet J 2006; 72:9397.

    • Search Google Scholar
    • Export Citation
  • 49.

    Saggi BH, Fisher RA, Bu RA, et al. Intragraft cytokine expression and tolerance induction in rat renal allografts. Transplantation 1999; 67:206210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50.

    Jiang H, Wynn C, Pan F, et al. Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production. Transplantation 2002; 73:18081817.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Daniel V, Naujokat C, Sadeghi M, et al. Association of circulating interleukin (IL)-12 and IL-10 producing dendritic cells with time posttransplant, dose of immunosupression, and plasma cytokines in renal-transplant recipients. Transplantation 2005; 79:14981506.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52.

    Wang SC, Zeevi A, Jordan ML, et al. FK506, rapamycin and cyclosporine: effects on IL-4 and IL-10 mRNA levels in a T helper 2 cell line. Transplant Proc 1991; 23:29202922.

    • Search Google Scholar
    • Export Citation
  • 53.

    Salicru AN, Sams CF, Marshall GD. Cooperative effects of corticosteroids and catecholamines upon immune deviation of the type-1/type-2 cytokine balance in favor of type-2 expression in human peripheral blood mononuclear cells. Brain Behav Immun 2007; 21:913920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54.

    Kuga K, Nishifuji K, Iwasaki T. Cyclosporine A inhibits transcription of cytokine genes and decreases the frequencies of IL-2 producing cells in feline mononuclear cells. J Vet Med Sci 2008; 70:10111016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Kim W, Cho ML, Kim SI, et al. Divergent effects of cyclosporine on Th1/Th2 type cytokines in patients with severe, refractory rheumatoid arthritis. J Rheumatol 2000; 27:324331.

    • Search Google Scholar
    • Export Citation
  • 56.

    Halloran PF, Leung Lui S. Approved immunosupressants. In: Primer on transplantation. Thorofare, NJ: American Society of Transplant Physicians, 1998;93102.

    • Search Google Scholar
    • Export Citation
  • 57.

    Kahan BD, Yoshimura N, Pellis NR, et al. Pharmacodynamics of cyclosporine. Transplant Proc 1986; 18(suppl 5):238251.

  • 58.

    Bessler H, Kagazanov S, Punsky I, et al. Effect of dexamethasone on IL-10 and Il-12p40 production in newborns and adults. Biol Neonate 2001; 80:262266.

  • 59.

    Torres KCL, Antonelli LRV, Souza ALS, et al. Norepinephrine, dopamine and dexamethasone modulate discrete leukocyte subpopulations and cytokine profiles from human PBMC. J Neuroimmunol 2005; 166:144157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60.

    Visser J, van Boxel-Dezaire A, Methorst D, et al. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood 1998; 91:42554264.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61.

    Martinez OM, Villanuera JC, Lawrence-Miyasaki L, et al. Viral and immunologic aspects of Epstein-Barr virus infection in pediatric liver transplant recipients. Transplantation 1995; 59:519524.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62.

    Stylianou E, Aukrust P, Kvale D, et al. IL-1 in HIV infection: increasing serum IL-10 levels with disease progression-down regulatory effects of potent anti-retroviral therapy. Clin Exp Immunol 1999; 116:115120.

    • Search Google Scholar
    • Export Citation
  • 63.

    Reuter H, Burgess LJ, Carstens ME, et al. Characterization of the immunological features of tuberculosis pericardial effusions in HIV positive and HIV negative patients in contrast with non-tuburculosis effusions. Tuberculosis 2006; 86:125133.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 64.

    Maxwell L, Singh JL. Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev 2009; 7:CD007277.

  • 65.

    Ponder KP, Wang B, Wang P, et al. Mucopolysaccharidosis I cats mount a cytotoxic T lymphocyte response after neonatal gene therapy that can be blocked with CTLA4-Ig. Mol Ther 2006; 14:513.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Effect of cyclosporine, dexamethasone, and human CTLA4-Ig on production of cytokines in lymphocytes of clinically normal cats and cats undergoing renal transplantation

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  • 1 Departments of Clinical Studies-Philadelphia
  • | 2 Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • | 3 Departments of Clinical Studies-Philadelphia
  • | 4 Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Abstract

Objective—To evaluate effects of cyclosporine, dexamethasone, and the immunosuppressive agent human CTLA4-Ig on cytokine production by feline lymphocytes in vitro and to assess patterns of cytokine production for 5 immunosuppressed renal transplant recipient cats.

Animals—21 clinically normal cats and 5 immunosupressed renal transplant recipient cats.

Procedures—Peripheral blood mononuclear cells were isolated from clinically normal cats and stimulated with concanavalin A (Con A; 10 μg/mL) alone or Con A with cyclosporine (0.05 μg/mL), dexamethasone (1 × 10−7M), a combination of cyclosporine-dexamethasone, or human CTLA4-Ig (10 g/mL). Cells from transplant recipients were stimulated with Con A alone. An ELISA was performed to measure production of interferon (IFN)-γ, granulocyte macrophage–colony stimulating factor (GM-CSF), interleukin (IL)-2, IL-4, and IL-10. Proliferation of CD4+ and CD8+T cells from immunosuppressed cats were also evaluated. Pairwise comparisons were performed via a Wilcoxon signed rank test or Wilcoxon rank sum test.

Results—Cyclosporine, dexamethasone, cyclosporine-dexamethasone combination, and CTLA4-Ig caused a significant decrease in IL-2, IFN-γ, and GM-CSF production. Cyclosporine and cyclosporine-dexamethasone, but not human CTLA4-Ig, caused a significant decrease in IL-10 production. High basal concentrations of IL-2 and IL-10 were identified in transplant recipients, and IL-10 was significantly increased in stimulated cultures. In immunosuppressed cats, there was a decrease in frequency of responders and proliferative capacity of CD4+ and CD8+T cells.

Conclusions and Clinical Relevance—CTLA4-Ig successfully inhibited proinflammatory cytokines while sparing cytokines critical for allograft tolerance. These data may be useful for developing better strategies to prevent rejection while sparing other immune functions.

Abstract

Objective—To evaluate effects of cyclosporine, dexamethasone, and the immunosuppressive agent human CTLA4-Ig on cytokine production by feline lymphocytes in vitro and to assess patterns of cytokine production for 5 immunosuppressed renal transplant recipient cats.

Animals—21 clinically normal cats and 5 immunosupressed renal transplant recipient cats.

Procedures—Peripheral blood mononuclear cells were isolated from clinically normal cats and stimulated with concanavalin A (Con A; 10 μg/mL) alone or Con A with cyclosporine (0.05 μg/mL), dexamethasone (1 × 10−7M), a combination of cyclosporine-dexamethasone, or human CTLA4-Ig (10 g/mL). Cells from transplant recipients were stimulated with Con A alone. An ELISA was performed to measure production of interferon (IFN)-γ, granulocyte macrophage–colony stimulating factor (GM-CSF), interleukin (IL)-2, IL-4, and IL-10. Proliferation of CD4+ and CD8+T cells from immunosuppressed cats were also evaluated. Pairwise comparisons were performed via a Wilcoxon signed rank test or Wilcoxon rank sum test.

Results—Cyclosporine, dexamethasone, cyclosporine-dexamethasone combination, and CTLA4-Ig caused a significant decrease in IL-2, IFN-γ, and GM-CSF production. Cyclosporine and cyclosporine-dexamethasone, but not human CTLA4-Ig, caused a significant decrease in IL-10 production. High basal concentrations of IL-2 and IL-10 were identified in transplant recipients, and IL-10 was significantly increased in stimulated cultures. In immunosuppressed cats, there was a decrease in frequency of responders and proliferative capacity of CD4+ and CD8+T cells.

Conclusions and Clinical Relevance—CTLA4-Ig successfully inhibited proinflammatory cytokines while sparing cytokines critical for allograft tolerance. These data may be useful for developing better strategies to prevent rejection while sparing other immune functions.

Contributor Notes

Address correspondence to Dr. Aronson (laronson@vet.upenn.edu).