Sex as a Biological Variable in Alloimmunity

• Applicant: Dr. Friederike Martin
• Subject Area: General and Visceral Surgery
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508048528

• Final Report Year: 2025

Final Report Abstract

Organ transplantation significantly extends the lives of patients with end-stage organ failure. However, there is a risk of post-transplant rejection, as the immune system may recognize the new organ as foreign. A key factor in this process is the formation of donor-specific antibodies (DSA), which specifically target the donor tissue. In our project, we investigate how recipient age and biological sex influence the development of such antibodies. To do this, we did bench research in an experimental mouse model of transplantation and analyzed human clinical data from a comprehensive kidney transplant registry in the United States. The human registry data show that older transplant candidates produce fewer antibodies than younger candidates. Additionally, female candidates are more likely than males to already have antibodies against potential donor organs prior to transplantation. In our mouse model, we similarly observe that older animals produce significantly fewer DSA after transplantation than young ones, regardless of recipient sex. In contrast, aged mice generate considerably more overall antibodies, which means antibodies not directed against the donor specifically. Here, we also observe a sex diVerence: female mice produce more non-specific antibodies than male mice, independent of age. To determine whether the diVerences in antibody production were due to the age and sex intrinsic to the B cell source or to the environment in which the cells function, we transferred B cells from young and old, male and female mice into B cell-deficient recipients. We found that even in a young host, B cells from aged animals still produced significantly fewer donor-specific antibodies after transplantation than young B cells. Further studies, including genetic analyses of B cells after transplantation by age and sex, are currently ongoing. Our findings demonstrate that age plays a key role in shaping the immune response and the formation of DSA before and after transplantation. Sex-associated diVerences in antibody development in human transplant candidates are likely influenced by diVering exposures to sensitizing events such as pregnancy in young adulthood and not only from inherent biological diVerences between the sexes. A better understanding of these age- and sex-dependent immune responses can improve interpretation of pretransplant antibody screenings, support more accurate immunological risk assessment, and help personalize immunosuppressive therapies, ultimately improving long-term graft and patient outcomes. The non-specific response of old B cells is also relevant beyond transplantation. A better understanding of the underlying mechanisms and approaches for their targeted modulation could help to improve the immune response of older people. This could make a relevant contribution to improving the prevention and treatment of immuneassociated diseases in older people.

Publications

• Oral presentation at the annully conference of the German Transplant Society (DTG) about “Chronic Rejection represents a process of accelerated aging that can be treated with the depletion of SCs and their SASP” on Saturday, Octorber 28, 2023 in Jena, Germany
  Friederike Martin
  
• Oral presentation at the annully conference of the German Transplant Society (DTG) about “Sex Hormones impact Transplant Outcomes through a modified DC - T Cell Communication” on Saturday, Octorber 28, 2023 in Jena, Germany
  Friederike Martin
  
• Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation. American Journal of Transplantation, 23(11), 1661-1672.
  Xiao, Yao; Schroeter, Andreas; Martin, Friederike; Matsunaga, Tomohisa; Nakamori, Keita; Roesel, Maximilian J.; Habal, Marlena; Chong, Anita S.; Zhou, Hao & Tullius, Stefan G.
  
• The Impact of T-cell Aging on Alloimmunity and Inflammaging. Transplantation, 108(3), 634-642.
  Iske, Jasper; Dedeilia, Aikaterini; Xiao, Yao; Martin, Friederike; Emmert, Maximilian Y.; Sage, Pete T.; Abdi, Reza; Zhou, Hao & Tullius, Stefan G.
  
• A new bicornuate model of rat uterus transplantation. Acta Obstetricia et Gynecologica Scandinavica, 104(3), 452-460.
  Polenz, Dietrich; Sauer, Igor Maximilian; Martin, Friederike; Reutzel‐Selke, Anja; Ashraf, Muhammad Imtiaz; Schirmeier, Anja; Lippert, Steffen; Führer, Kirsten; Pratschke, Johann; Tullius, Stefan Günther & Moosburner, Simon
  
• Invited presentation for the 30th international Congress of The Transplant Society (TTS) Women in Transplantation Satellite Symposium Mission & Vision of Women in Transplantation, on Sunday, September 22, 2024 in Instanbul, Turkey
  Friederike Martin
  
• Obesity-associated Inflammation and Alloimmunity. Transplantation, 109(4), 588-596.
  Zhou, Hao; Gizlenci, Merih; Xiao, Yao; Martin, Friederike; Nakamori, Keita; Zicari, Elizabeth M.; Sato, Yuko & Tullius, Stefan G.
  
• Oral presentation at the 141st annual Congress of the German Society of Surgery (DCK) about “Aging is transferable: Old Organs Accelerate Aging and Induce Senescence in Young Recipients” on April 24, 2024 in Leipzig, Deutschland
  Friederike Martin
  
• Oral presentations at the 30th international Congress of The Transplant Society (TTS) 2024 about “Panel Reactive Antibody Levels decline with increasing Age: Potential of augmented Organ Availability and improved Outcomes for sensitized older Recipients” on Monday, September 23, 2024 in Instanbul, Turkey
  Friederike Martin
  
• Oral presentations at the 30th international Congress of The Transplant Society (TTS) 2024 about “Reassessing the Determination of Sensitization Status in Kidney Transplant Candidates: Unveiling persistent Anti-HLA Antibodies in waitlisted Patients” on Tueasday, September 24, 2024 in Instanbul, Turkey
  Friederike Martin
  
• Presentation at the American Transplant Congress (ATC) 2024 “Sex Modulates the Age-Related Decline in Sensitization among Deceased Donor Kidney Transplant Candidates” on June 1, 2024 in Philadelphia, USA
  Friederike Martin
  
• The combinatorial effect of age and biological sex on alloimmunity and transplantation outcome. Frontiers in Transplantation, 2.
  Martin, Friederike; Xiao, Yao; Welten, Vanessa; Nakamori, Keita; Gizlenci, Merih; Zhou, Hao & Tullius, Stefan G.
  
• Transplanting old organs promotes senescence in young recipients. American Journal of Transplantation, 24(3), 391-405.
  Iske, Jasper; Roesel, Maximilian J.; Martin, Friederike; Schroeter, Andreas; Matsunaga, Tomohisa; Maenosono, Ryoichi; Tripathi, Utkarsh; Xiao, Yao; Nian, Yeqi; Caldarone, Barbara J.; Vondran, Florian W.R.; Sage, Peter T.; Azuma, Haruhito; Abdi, Reza; Elkhal, Abdallah; Pirtskhalava, Tamar; Tchkonia, Tamara; Kirkland, James L.; Zhou, Hao & Tullius, Stefan G.
  
• Invited speaker at the World Transplant Congress (WTC) 2025 on Saturday, August 2, 2025 in San Francisco about the “Impact of Hormones and Hormonal Receptors on Alloimmunity”
  Friederike Martin
  
• Oral presentation at the World Transplant Congress (WTC) 2025 about “Historically Reported Donor Specific Antibodies Rather Than Current Should Be Used to Assess Immunological Risk after Kidney Transplant (KTx)”
  Friederike Martin
  
• Presentation at the World Transplant Congress (WTC) 2025 about “Age and Sex Are Critical in Driving Humoral Alloimmune Response”
  Friederike Martin