Cardiovascular Research

Recipient sex and estradiol levels affect transplant outcomes in an age-specific fashion.

Authors: Ryoichi Maenosono|||Yeqi Nian|||Jasper Iske|||Yang Liu|||Koichiro Minami|||Tabea Rommel|||Friederike Martin|||Reza Abdi|||Haruhito Azuma|||Bernhard A Rosner|||Hao Zhou|||Edgar Milford|||Abdallah Elkhal|||Stefan G Tullius

Affiliations: + Expand

Abstract

Sex-specific influences have been shown for a variety of diseases. Whether donor or recipient sex and sex hormone levels impact alloimmune responses remains unclear. In unifactorial and multifactorial analyses of more than 400 000 SRTR listed kidney transplant patients, we found that younger female recipients had an inferior death-censored graft survival that was independent of donor sex. In contrast, graft survival was superior in older female recipients, suggesting the impact of recipient sex hormones over chromosomal sex mismatches. Those clinical changes were delineated in experimental skin and heart transplant models showing a prolongation of graft survival in ovariectomized young female recipients. In contrast, graft survival was comparable in ovariectomized and naïve old female recipients. Young ovariectomized mice showed reduced amounts and a compromised T cell proliferation. Deprivation of female hormones dampened the production of interferon (IFN)-γ and interleukin (IL)-17 by CD4 T cells while augmenting systemic counts of Tregs. Increasing estradiol concentrations in vitro promoted the switch of naïve CD4 T cells into Th1 cells; high physiological estradiol concentrations dampening Th1 responses, promoted Tregs, and prolonged graft survival. Thus, clinical observations demonstrate age-specific graft survival patterns in female recipients. Estrogen levels, in turn, impact the fate of T cell subsets, providing relevant and novel information on age- and sex-specific alloimmunity.

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Chemical List

Estradiol

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Reference List

Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014;35(3):347–369.|||Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev 2017;97(1):1–37.|||Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res 2017;95(1–2):671–680.|||McClelland EE, Smith JM. Gender specific differences in the immune response to infection. Arch Immunol Ther Exp (Warsz) 2011;59(3):203–213.|||Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 2020;11(1):29.|||Berger JS, Elliott L, Gallup D, Roe M, Granger CB, Armstrong PW et al. Sex differences in mortality following acute coronary syndromes. JAMA 2009;302(8):874–882.|||Hanamsagar R, Bilbo SD. Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development. J Steroid Biochem Mol Biol 2016;160:127–133.|||Oyola MG, Handa RJ. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress 2017;20(5):476–494.|||Nelson HD. Menopause. Lancet 2008;371(9614):760–770.|||Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW. Hormonal profiles after the menopause. Br Med J 1976;2(6039):784–787.|||Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFN-gamma promoter. J Immunol 1991;146(12):4362–4367.|||Karpuzoglu-Sahin E, Hissong BD, Ansar Ahmed S. Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol 2001;52(1–2):113–127.|||Karpuzoglu E, Phillips RA, Gogal RM Jr., Ansar Ahmed S. IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12. Mol Immunol 2007;44(7):1808–1814.|||Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy 2004;3(1):97–104.|||Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 2004;173(4):2227–2230.|||Lau A, West L, Tullius SG. The Impact of Sex on Alloimmunity. Trends Immunol 2018;39(5):407–418.|||Brenner BM, Milford EL. Nephron underdosing: a programmed cause of chronic renal allograft failure. Am J Kidney Dis 1993;21(5 Suppl 2):66–72.|||Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13(10):2570–2576.|||Schoening WN, Helbig M, Buescher N, Andreou A, Bahra M, Schmitz V et al. Gender Matches in Liver Transplant Allocation: Matched and Mismatched Male-Female Donor-Recipient Combinations; Long-term Follow-up of More Than 2000 Patients at a Single Center. Exp Clin Transplant 2016;14(2):184–190.|||Tan JC, Kim JP, Chertow GM, Grumet FC, Desai M. Donor-recipient sex mismatch in kidney transplantation. Gend Med 2012;9(5):335–347 e332.|||Kim SJ, Gill JS. H-Y incompatibility predicts short-term outcomes for kidney transplant recipients. J Am Soc Nephrol 2009;20(9):2025–2033.|||Gratwohl A, Dohler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008;372(9632):49–53.|||Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996;334(5):281–285.|||Haynes L, Maue AC. Effects of aging on T cell function. Curr Opin Immunol 2009;21(4):414–417.|||Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med 2011;364(14):1369–1370.|||Quante M, Heinbokel T, Edtinger K, Minami K, Uehara H, Nian Y et al. Rapamycin Prolongs Graft Survival and Induces CD4+IFN-gamma+IL-10+ Regulatory Type 1 Cells in Old Recipient Mice. Transplantation 2018;102(1):59–69.|||Krenzien F, Quante M, Heinbokel T, Seyda M, Minami K, Uehara H et al. Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus. Am J Transplant 2017;17(5):1242–1254.|||Matsumoto YK, Kasai M, Tomihara K. The enhancement effect of estradiol on contextual fear conditioning in female mice. PLoS One 2018;13(5):e0197441.|||Ingberg E, Theodorsson A, Theodorsson E, Strom JO. Methods for long-term 17beta-estradiol administration to mice. Gen Comp Endocrinol 2012;175(1):188–193.|||Koebele SV, Bimonte-Nelson HA. Modeling menopause: The utility of rodents in translational behavioral endocrinology research. Maturitas 2016;87:5–17.|||Diaz Brinton R. Minireview: translational animal models of human menopause: challenges and emerging opportunities. Endocrinology 2012;153(8):3571–3578.|||Zou Y, Steurer W, Klima G, Obrist P, Margreiter R, Brandacher G. Estradiol enhances murine cardiac allograft rejection under cyclosporin and can be antagonized by the antiestrogen tamoxifen. Transplantation 2002;74(3):354–357.|||Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007;28(5):521–574.|||Nilsson ME, Vandenput L, Tivesten A, Norlen AK, Lagerquist MK, Windahl SH et al. Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry. Endocrinology 2015;156(7):2492–2502.|||Xiu F, Anipindi VC, Nguyen PV, Boudreau J, Liang H, Wan Y et al. High Physiological Concentrations of Progesterone Reverse Estradiol-Mediated Changes in Differentiation and Functions of Bone Marrow Derived Dendritic Cells. PLoS One 2016;11(4):e0153304.|||Pazos MA, Kraus TA, Munoz-Fontela C, Moran TM. Estrogen mediates innate and adaptive immune alterations to influenza infection in pregnant mice. PLoS One 2012;7(7):e40502.|||Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL. 17beta-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. J Virol 2014;88(9):4711–4720.|||Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3(2):162–169.|||Khan D, Ansar Ahmed S. The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases. Front Immunol 2015;6:635.|||Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003;38(1):13–22.|||Iske J, Seyda M, Heinbokel T, Maenosono R, Minami K, Nian Y et al. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat Commun 2020;11(1):4289.|||Heinbokel T, Quante M, Iske J, Nian Y, Maenosono R, Minami K et al. CTLA4-Ig prolongs graft survival specifically in young but not old mice. Am J Transplant 2020.|||Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology 2009;150(8):3877–3884.|||Paharkova-Vatchkova V, Maldonado R, Kovats S. Estrogen preferentially promotes the differentiation of CD11c+ CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol 2004;172(3):1426–1436.|||Bengtsson AK, Ryan EJ, Giordano D, Magaletti DM, Clark EA. 17beta-estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells. Blood 2004;104(5):1404–1410.|||Cunningham MA, Wirth JR, Scott JL, Eudaly J, Collins EL, Gilkeson GS. Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+ Spleen Cells and Impacts Disease Expression in Murine Lupus. Front Immunol 2016;7:31.|||Weinstein Y, Ran S, Segal S. Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. J Immunol 1984;132(2):656–661.|||Pelfrey CM, Cotleur AC, Lee JC, Rudick RA. Sex differences in cytokine responses to myelin peptides in multiple sclerosis. J Neuroimmunol 2002;130(1–2):211–223.|||Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 2009;10(5):509–516.|||Haghmorad D, Amini AA, Mahmoudi MB, Rastin M, Hosseini M, Mahmoudi M. Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J Neuroimmunol 2014;277(1–2):85–95.|||Sinclair M, Gow PJ, Grossmann M, Shannon A, Hoermann R, Angus PW. Low serum testosterone is associated with adverse outcome in men with cirrhosis independent of the model for end-stage liver disease score. Liver Transpl 2016;22(11):1482–1490.|||Antus B, Yao Y, Liu S, Song E, Lutz J, Heemann U. Contribution of androgens to chronic allograft nephropathy is mediated by dihydrotestosterone. Kidney Int 2001;60(5):1955–1963.|||Zou YP, Brandacher G, Obrist P, Margreiter R, Steurer W. Tamoxifen prolongs heart allograft survival in cyclosporine-treated female mice. Transplant Proc 1999;31(1–2):1222–1223.|||Walter P, Green S, Greene G, Krust A, Bornert JM, Jeltsch JM et al. Cloning of the human estrogen receptor cDNA. Proc Natl Acad Sci U S A 1985;82(23):7889–7893.|||Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986;320(6058):134–139.|||Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996;93(12):5925–5930.|||Bebo BF Jr., Schuster JC, Vandenbark AA, Offner H. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol 1999;162(1):35–40.|||Jansson L, Olsson T, Holmdahl R. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J Neuroimmunol 1994;53(2):203–207.|||Trooster WJ, Teelken AW, Kampinga J, Loof JG, Nieuwenhuis P, Minderhoud JM. Suppression of acute experimental allergic encephalomyelitis by the synthetic sex hormone 17-alpha-ethinylestradiol: an immunological study in the Lewis rat. Int Arch Allergy Immunol 1993;102(2):133–140.|||Polanczyk M, Zamora A, Subramanian S, Matejuk A, Hess DL, Blankenhorn EP et al. The protective effect of 17beta-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-alpha. Am J Pathol 2003;163(4):1599–1605.|||Morales LB, Loo KK, Liu HB, Peterson C, Tiwari-Woodruff S, Voskuhl RR. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis. J Neurosci 2006;26(25):6823–6833.|||Kim WU, Min SY, Hwang SH, Yoo SA, Kim KJ, Cho CS. Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol 2010;161(3):453–458.|||Polese B, Gridelet V, Araklioti E, Martens H, Perrier d’Hauterive S, Geenen V. The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy. Front Endocrinol (Lausanne) 2014;5:106.|||Khan D, Dai R, Karpuzoglu E, Ahmed SA. Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice. Eur J Immunol 2010;40(9):2549–2556.