Aging and alloimmunity
Metabolism and Alloimmunity
Sex as a Biological Variable
Aging and alloimmunity
- Rejuvenating old organs
- Defining the aging in immune response
- Transfer of aging
We have made substantial progress defining mechanistic aspects that linking aging to alloimmune response. Overall, our studies suggest that elderly recipients respond to alloantigens and immunosuppression in an age-specific fashions. We have demonstrated that: a). old DCs communicate an augmented Th17-driven alloimmune response; b). old CD8 T cells have compromised production and IFN-γ, defective IL-2R signaling and malfunctioning communication with DCs; c). tacrolimus interferes age-specifically with both human and murine CD4 T cells by suppressing CD4 T cell proliferation, IL-2 and IFN-γ production; while promoting IL-10 production; d). rapamycin promotes graft survival in elderly recipients through augmented IL-10 levels; e). immunosuppresive capacity of CLTA4-Ig is compromised in elderly recipients because of an age-specific expression of CD28 on effector memory and regulatory T cells; f). both old human and mouse CD4 T cells rely heavily on glutaminolysis, leading to the inhibition of glutamate metabolism pathway specifically prolonged graft survival in elderly recipients.
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- Nian Y, Iske J, Maenosono R, Minami K, Heinbokel T, Quante M, Liu Y, Azuma H, Yang J, Abdi R, Zhou H, Elkhal A, Tullius SG. Targeting age-specific changes in CD4<sup>+</sup> T cell metabolism ameliorates alloimmune responses and prolongs graft survival. Aging Cell. 2021 Feb;20(2):e13299. doi: 10.1111/acel.13299. Epub 2021 Jan 26. PMID: 33497523; PMCID: PMC7884034
- Iske J, Matsunaga T, Zhou H, Tullius SG. Donor and Recipient Age-Mismatches: The Potential of Transferring Senescence. Front Immunol. 2021 Apr 28;12:671479. doi: 10.3389/fimmu.2021.671479. PMID: 33995411; PMCID: PMC8113632.
- Iske J, Hinze CA, Salman J, Haverich A, Tullius SG, Ius F. The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury. Am J Transplant. 2021 Aug 6. doi: 10.1111/ajt.16784. Epub ahead of print. PMID: 34355495.
- Iske J, Seyda M, Heinbokel T, Maenosono R, Minami K, Nian Y, Quante M, Falk CS, Azuma H, Martin F, Passos JF, Niemann CU, Tchkonia T, Kirkland JL, Elkhal A, Tullius SG. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat Commun. 2020 Aug 27;11(1):4289. doi: 10.1038/s41467-020-18039-x. PMID: 32855397; PMCID: PMC7453018.
- Heinbokel T, Quante M, Iske J, Nian Y, Maenosono R, Minami K, Liu Y, Azuma H, Elkhal A, Tullius SG. CTLA4-Ig prolongs graft survival specifically in young but not old mice. Am J Transplant. 2020 Jul 27. doi: 10.1111/ajt.16218. Epub ahead of print. PMID: 32717114.
- Tullius SG, Rabb H. Improving the Supply and Quality of Deceased-Donor Organs for Transplantation. N Engl J Med. 2018 May 17;378(20):1920-1929. doi: 10.1056/NEJMra1507080. PMID: 29768153.
- Quante M, Heinbokel T, Edtinger K, Minami K, Uehara H, Nian Y, Azuma H, Abdi R, Elkhal A, Tullius SG. Rapamycin Prolongs Graft Survival and Induces CD4+IFN-γ+IL-10+ Regulatory Type 1 Cells in Old Recipient Mice. Transplantation. 2018 Jan;102(1):59-69. doi: 10.1097/TP.0000000000001902. PMID: 28777210; PMCID: PMC5741485.
Krenzien F, Quante M, Heinbokel T, Seyda M, Minami K, Uehara H, Biefer HR, Schuitenmaker JM, Gabardi S, Splith K, Schmelzle M, Petrides AK, Azuma H, Pratschke J, Li XC, ElKhal A, Tullius SG. Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus. Am J Transplant. 2016 Oct 18.
Seyda M, Elkhal A, Quante M, Falk CS, Tullius SG. T Cells Going Innate. Trends Immunol. 2016 Aug; 37(8):546-56.
- Tullius SG. Vascular composite tissue transplantation: achievements and challenges in a rapidly developing field. Transpl Int. 2016 Jun;29(6):643.
- Mukundan S, Steigner ML, Hsiao LL, Malek SK, Tullius SG, Chin MS, Siedlecki AM. Ferumoxytol-Enhanced Magnetic Resonance Imaging in Late-Stage CKD. Am J Kidney Dis. 2016 Jun;67(6):984-8.
- Chandraker A, Arscott R, Murphy G, Lian C, Bueno E, Marty F, Rennke H, Milford E, Tullius S, Pomahac B. Face Transplantation in a Highly Sensitized Recipient. Mil Med. 2016 May;181(5 Suppl):221-6.
- Aycart MA, Alhefzi M, Sharma G, Krezdorn N, Bueno EM, Talbot SG, Carty MJ, Tullius SG, Pomahac B. Outcomes of Solid Organ Transplants After Simultaneous Solid Organ and Vascularized Composite Allograft Procurements: A Nationwide Analysis. Transplantation. 2016 May 2.
- Gabardi S, Tullius SG, Krenzien F.Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly. Curr Opin Organ Transplant. 2015 Aug;20(4):424-30.
- Exterkate L, Slegtenhorst BR, Seyda M, Schuitenmaker JM, Quante M, Uehara H, El Khal A, Tullius SG. Frailty and Transplantation. 2015 Dec 22.
- Krenzien F, ElKhal A, Quante M, Rodriguez Cetina Biefer H, Hirofumi U, Gabardi S, Tullius SG. A Rationale for Age-Adapted Immunosuppression in Organ Transplantation. Transplantation. 2015;99(11):2258-68.
- Seyda M, Quante M, Uehara H, Slegtenhorst BR, Elkhal A, Tullius SG. Immunosenescence in renal transplantation: a changing balance of innate and adaptive immunity. Curr Opin Organ Transplant. 2015; 20(4):417-23.
- Hernandez RA, Malek SK, Milford EL, Finlayson SR, Tullius SG. The combined risk of donor quality and recipient age: higher-quality kidneys may not always improve patient and graft survival. Transplantation. 2014; 98(10):1069-76.
- Slegtenhorst BR, Dor FJ, Elkhal A, Rodriguez H, Yang X, Edtinger K, Quante M, Chong AS, Tullius SG. Mechanisms and consequences of injury and repair in older organ transplants. Transplantation. 2014;15;97(11):1091-9.
- Hock K, Oberhuber R, Lee YL, Wrba F, Wekerle T, Tullius SG.: Immunosenescence does not abrogate engraftment of murine allogenic bone marrow. Transplantation. 2013; 95(12):1431-8.
- Oberhuber R, Ge X, Tullius SG. Donor age-specific injury and immune responses. Am J Transpl, 2012: 12(1):38-42.
- Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med. 2011; 364 (14): 1369-70.
- Tullius S.G., Tran H, Guleria I, Malek S, Tilney N, Milford E. The combination of Donor and Recipient Age is critical in determining host immunoresponsiveness and renal transplant outcome. Ann Surg. 2010; 252:662-74.
- Denecke C, Bedi DS, Ge X, Kim IK, Jurisch A, Weiland A, Habicht A, Li XC, Tullius SG. Prolonged graft survival in older recipient mice is determined by impaired effector T-cell but intact regulatory T-cell responses. PLoS One. 2010; 5:2.
Metabolism and Alloimmunity
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- Quante M, Iske J, Heinbokel T, Desai BN, Cetina Biefer HR, Nian Y, Krenzien F, Matsunaga T, Uehara H, Maenosono R, Azuma H, Pratschke J, Falk CS, Lo T, Sheu E, Tavakkoli A, Abdi R, Perkins D, Alegre ML, Banks AS, Zhou H, Elkhal A, Tullius SG. Restored TDCA and valine levels imitate the effects of bariatric surgery. Elife. 2021 Jun 22;10:e62928. doi: 10.7554/eLife.62928. PMID: 34155969; PMCID: PMC8257250.
- Quante M, Dietrich A, ElKhal A, Tullius SG. Obesity-related immune responses and their impact on surgical outcomes. Int J Obes (Lond). 2015: 39(6): 877-83.
Sex as a Biological Variable
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- Maenosono R, Nian Y, Iske J, Liu Y, Minami K, Rommel T, Martin F, Abdi R, Azuma H, Rosner BA, Zhou H, Milford E, Elkhal A, Tullius SG. Recipient sex and estradiol levels affect transplant outcomes in an age-specific fashion. Am J Transplant. 2021 May 28. doi: 10.1111/ajt.16611. Epub ahead of print. PMID: 34050595.
- Lau A, West L, Tullius SG. The Impact of Sex on Alloimmunity. Trends Immunol. 2018 May;39(5):407-418. doi: 10.1016/j.it.2018.01.008. Epub 2018 Mar 22. PMID: 29576409