Aging in Organ Transplantation

The aging global population has had a significant effect on organ transplantation.  Over the last decade, the number of patients > age 65 on the waiting listed for an organ transplant has tripled.  Moreover, to meet the ever increasing demand, more marginal organs are being used for transplantation.

The phenomenon of an age-dependent immune response to exogenous antigens is termed immunosenescence. Clinical studies show broad effects of immunosenescence on all immune compartments with relevance for transplantation. Therefore, a detailed comprehension of immunological alterations with aging bears the potential of adapting immunosuppression, or to utilize physiological aspects of immunosenescence to modulate immune responses.

Older organs are not only more sensitive to injury, they also have an augmented immunogenicity that shapes immune responses after transplantation. Our lab investigates these mechanisms with the goal to improve treatment and to increase the utilization of older organs.

Altered Graft Infiltration Pattern In Old Hearts

Obesity and Transplantation

The global prevalence of overweight and obesity has shown a dramatic increase and represents a challenge in transplantation medicine. The prevalence of obesity (BMI ≥ 30) among kidney allograft recipients has reached 30%.  Despite a growing number of clinical reports of inferior outcomes and higher complication rates in obese transplant recipients, a more profound understanding of the obesity-related changes to immune responses relevant to organ transplantation is still lacking.

Recent evidence has conceptualized obesity as a chronic inflammatory condition. Of additional clinical relevance in transplantation, some reports have shown more frequent acute rejections and augmented allograft immunogenicity in obese recipients. Although it is known that obesity promotes inflammation, very little is known about the impact of the condition on the immune response.

In our lab, we explore the impact of obesity on immune responses. We have shown that obesity accelerates rejection. Bariatric surgery, at the same time prolongs graft survival. We are now studying targets that are detected subsequent to bariatric surgery and exploring their potential in modifying alloimmune responses and weight loss.

 

Gastric Sleeve Procedure

a) Intra-operative field. b) Creating the gastric sleeve using a clamp. c) Gastric sleeve after completion of the procedure. d) Surgical specimen of the removed gastric part. (* esophagus, D duodenum, FS forestomach, GS glandular stomach)click for image details
a) Intra-operative field. b) Creating the gastric sleeve using a clamp. c) Gastric sleeve after completion of the procedure. d) Surgical specimen of the removed gastric part. (* esophagus, D duodenum, FS forestomach, GS glandular stomach)

Role of NAD+ in Immune Regulation

A better understanding of the causes of the alteration in immune responses during inflammation has the potential to unravel new targets that will pave the way for novel therapeutic approaches.

Using disease animal models that reflect human pathology/inflammation, including autoimmune disease and transplantation, our lab has shown that the natural cofactor NAD+ is able to regulate CD4+ T cell differentiation independently of cytokine milieu and well established transcription factiors. Building on this finding, our laboratory is working to elucidate the role of NAD+ in two distinct aspects:

  1. The role of NAD+ as a regulator of the immune system
  2. The clinical therapeutic potential of NAD+ during inflammatory responses

NAD+ enhances ependymal cell proliferation and Musashi expression

NAD + treatment significantly increased Ki67 (b) and Musashi (d) labeling in ependymal cell population (1), subependymally and in outer circumference of the spinal cord (2 ) when compared to controls (a, c).click for image details
NAD + treatment significantly increased Ki67 (b) and Musashi (d) labeling in ependymal cell population (1), subependymally and in outer circumference of the spinal cord (2 ) when compared to controls (a, c).

Adaptive Features in Innate Immunity and Transplantation

The immune system has traditionally been divided into innate immune cells and adaptive immune cells.  Innate immune cells have been considered short-lived, with the capacity to respond rapidly and in a non-specific fashion.  Adaptive immune cells have been characterized as having a highly specific response initiated in a delayed fashion. Although immunological memory has generally been considered as exclusive to the adaptive immune responses of T cells and B cells, recent studies have demonstrated that innate immune cells also have the potential to acquire memory.

Recent studies have indicated that activated NK cells and macrophages participate in the immune response after transplantation. Despite these intriguing findings, our knowledge on the adaptive features of innate immune cells remains in its infancy, and the mechanisms of antigen recognition as part of a memory function remain unclear.

An enhanced understanding of the adaptive features of innate immunity should contribute to a broader knowledge of host defenses and has the potentianl to lead to the development of novel immunotherapeutic approaches in organ transplantation. Our lab seeks to advance this understanding.

Adaptive immune responses appear to shift to a more dominant innate immune response in aging, immunosuppression or –exhaustion.  We have now evidence that those aspects are of relevance in transplantation and dissect these mechanisms in our experimental model.

Recipient Age Prolongs Allograft Survival

Effects of the aging immune system on the recipient's alloimmune response by engrafting 18mths B6 mice with bm12 skin transplants. Although old recipients showed a significantly delayed graft rejection compared to young recipients, CD4+ T-cell infiltrates were however comparable by day 7 following transplantation.click for image details
Effects of the aging immune system on the recipient's alloimmune response by engrafting 18mths B6 mice with bm12 skin transplants. Although old recipients showed a significantly delayed graft rejection compared to young recipients, CD4+ T-cell infiltrates were however comparable by day 7 following transplantation.

Endothelial Injury During Organ Preservation

During preservation, organs for transplantation are temporarily deprived of blood flow and nutritional support. The vascular endothelium, a cell layer located between the blood vessel wall and lumen, acquires a vasoprotective phenotype in response to pulsatile blood flow.

Long-standing collaborative efforts with the García-Cardeña Laboratory (PI: Guillermo Garcia-Cardeña, Director of the Laboratory for Systems Biology at the Center for Excellence in Vascular Biology, BWH), have established that the endothelium becomes dysfunctional subsequent to the cessation of flow, promoting processes such as coagulation and inflammation that negatively impact organ quality and accelerate alloimmune responses.

In a continuation of this collaboration, we are currently moving from the identification of general vascular descriptors to an analysis of endothelial molecular pathways that induce a flow mediated vasoprotective phenotype. With this approach we expect to characterize novel molecular targets responsible for maintaining endothelial function, and improve organ preservation.

KLF2 localization by in-situ hybridization on endothelial cells of the murine aorta.

click for image details
Simvastatin maintains the expression of endothelial KLF2 and its vasoprotective target genes during cold storage ex vivo.