Older individuals show the highest proportional increase of those being waitlisted or receiving an organ transplant. The increasing need has been compensated, at least in part, by utilizing older donor organs. Aging is associated with significant changes of the immune system, but little is known about underlying mechanisms and the potential impact on immune responses in organ transplantation. Moreover, little is known on how organ age may impact immune responses. We have shown in a large scale clinical study that older renal transplant recipients had less acute rejections and a better (death censored) graft survival. In contrast, engraftment of older organs had been linked with significantly more acute rejections. In a bed-to-bench approach, we have recently reported experimental data showing that advanced donor age was associated with significantly higher frequencies of activated T cells, an intensified T-cell proliferation and alloreactive IFNg production. We have now also established an experimental transplant model that shows a significantly shorter survival of old allografts. Recipient age, in our experimental studies delayed graft rejection and was associated with impaired T cell responses, reduced T-cell proliferation and limited IFNg production. At the same time, we observed a well preserved suppressor function of old alloantigen-specific CD4+CD25+FoxP3+ T cells. Our preliminary experimental data in old recipients have also shown an alteration of the CD8+ TCR signaling machinery that was associated with a down-regulation of CD122. We were also able to show experimentally that immunouppressants have age-specific effects: treatment of old and young recipient mice with rapamycin or CTLA4-Ig, two clinically relevant immunosuppressants that have different mechanisms of action showed age-dependent effects on allograft survival. Rapamycin promoted long-term graft function in old recipients while cardiac allografts in young recipients showed a significantly reduced survival. In contrast, treatment with CTLA4-Ig promoted graft survival in young but not old recipients. In this application, we will dissect mechanisms of age-specific alloimmune responses.
In specific aim 1, we will identify whether aging augments the immunogenic capacity of donor dendritic cells (DCs). Moreover, we will define the role of old DCs in allograft rejection that is associated with aging using DTR transgenic mice and identify activating signaling pathway(s).
In specific aim 2, we will assess functional changes of CD4+ and CD8+ T cells in old and young mice. Moreover, we will test in-vivo proliferation and conversion of effector T cells into Tregs using Foxp3-GFP reporter transgenic mice.
In specific aim 3, we will define age-specific responses to rapamycin and CTLA4-Ig. As our society is embracing an expanding aging population our studies will be of considerable significance and will allow creating effective therapeutic protocols with relevance in and beyond organ transplantation.

Public Health Relevance

This research is relevant to public health because it addresses the impact of aging on immune cells (T and APC cells) and solid organ transplant survival. Therefore, this study is important because it is novel and it will permit us to develop effective and new therapies to prevent allograft rejection in elderly patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG039449-02
Application #
8554746
Study Section
Special Emphasis Panel (ZRG1-IMM-N (02))
Program Officer
Fuldner, Rebecca A
Project Start
2012-09-30
Project End
2017-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$288,521
Indirect Cost
$94,796
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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