Monday September 14, 2020 - 14:30 to 15:15
Transplantation of older organs transfers senescence
Jasper Iske1,2, Ryoichi Maenosono1,3, Midas Seyda1,2, Timm Heinbokel1,4, Koichiro Minami1,3, Yeqi Nian1,5, Haruhito Azuma3, Reza Abdi6, Tamar Tchkonia7, James L. Kirkland7, Abdallah Elkhal1, Stefan G. Tullius1.
1Department of Surgery, Brigham and Women's Hospital , Boston, MA, United States; 2Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany; 3Department of Urology, Osaka Medical College, Osaka, Japan; 4Department of Nephrology, Charite Universitätsmedizin Berlin, Berlin, Germany; 5Department of Kidney Transplantation, Tianjin First Central Hospital, Tianjin, People's Republic of China; 6Transplantation Research Center, Brigham and Women's Hospital, Boston, MA, United States; 7Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States
Introduction: Organ age is linked to an accumulation of senescent cells that induce a senescent phenotype in neighboring cells through alterations of the immune-micro-environment. Organ age has also been shown to augment alloimmune responses in recipients resulting into increased acute rejection rates. We hypothesized that senescent cells disseminate in recipients subsequent to the engraftment of older organs and postulated an acceleration in aging.
Material and Methods: Hearts from either young or old C57BL/6 (2 and 18 months) were transplanted into syngeneic and allogeneic young recipients. Solid organs and lymphoid tissues were collected from donors and recipients at sequential intervals after engraftment, assessing the distribution of senescent cells and inflammatory products; systemic and local senescent associated secretory phenotype (SASP) derived molecules (mt-DNA, p16) were measured by qPCR. T cell and DC frequency and activation were tested by FACS and co-culturing experiments. Donors were treated with senolytics (Dasitinib & Quercetin) prior to organ procurement and cardiac transplantation into histoincompatible recipients.
Results: We detected an increased frequency of senescent cells in hearts, kidneys and skin of old donor mice (mean= 8,21% vs 0,3% in organs from young animals). More importantly, young recipients of old cardiac allografts demonstrated increased frequencies of senescent cells (by post-operative day 30) localized in draining lymph nodes and livers (3,1-fold and 20.3 fold increase, p<0.01 and p<0.0001 compared to young recipients of young hearts); young recipients of old grafts also showed augmented systemic p16 levels indicating a spread of the senescent phenotype (3,45-fold increase, p< 0.05). As part of the SASP, isolated senescent cells released significantly increased amounts of mt-DNA (p<0.05) that augmented co-stimulatory molecule expression in old dendritic cells in-vitro enhancing Th17 and Th1 derived cytokine expression. Treatment of old donor animals with senolytics disabling senescence-associated anti-apoptotic pathways cleared senescent cells and reduced mt-DNA and p16 levels (p=0.01 compared to young controls). Moreover, senolytics restricted the expression of IFN-γ and IL-17 on CD4+ T cells (p=0.001) and prolonged the survival of old cardiac allografts significantly (p=0.02).
Conclusion: The accumulation of senescent cells in old organs accelerated alloimmune responses through augmented mt-DNA levels. Notably, transplanting older organs promoted senescence in transplant recipients. Senolytics cleared senescent cells, dampened alloimmune responses and prolonged allograft survival. Those data may serve as a rationale to utilize senolytics to improve graft quality and survival of older organs. Moreover, senolytics may halt the spread of senescent cells in recipients of old organs.