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.

Metabolism and Alloimmunity

Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity and has been recommended for morbidly obese transplant recipients. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in Diet-Induced-Obese (DIO) mice.  TDCA and L-Valine levels were restored after sleeve gastrectomies (SGx) in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Allograft survival was significantly shorter in obese mice. When performing SGx prior to transplantation, we found significantly attenuated T cell-derived alloimmune responses and prolonged allograft survival comparable to that in lean mice.

Sex as a Biological Variable

Biological sex has an influence on a variety of physiological and pathological processes showing sex dependent differences in the occurrence of several diseases (e.g. autoimmune diseases more often in women, men more susceptible to infectious diseases). In organ transplantation, donor and recipient sex are known to affect transplantation outcome. Women, receiving a kidney or heart transplant from male donors show inferior graft survival.