Damanpreet Singh Bedi

Animal models of chronic allograft injury: contributions and limitations to understanding the mechanism of long-term graft dysfunction.

Advances in immunosuppression have reduced the incidence of acute graft loss after transplantation, but long-term allograft survival is still hindered by the development of chronic allograft injury, a multifactorial process that involves both immunologic and nonimmunologic components. Because these components become defined in the clinical setting, development of animal models enables exploration into underlying mechanisms leading to long-term graft dysfunction. This review presents animal models that have enabled investigation into chronic allograft injury and discusses pivotal models currently being used. The mechanisms uncovered by these models will ultimately lead to development of new therapeutic options to prevent long-term graft dysfunction.

Prolonged Graft Survival in Older Recipient Mice Is Determined by Impaired Effector T-Cell but Intact Regulatory T-Cell Responses

Elderly organ transplant recipients represent a fast growing segment of patients on the waiting list. We examined age-dependent CD4+ T-cell functions in a wild-type (WT) and a transgenic mouse transplant model and analyzed the suppressive function of old regulatory T-cells. We found that splenocytes of naïve old B6 mice contained significantly higher frequencies of T-cells with an effector/memory phenotype (CD4+CD44highCD62Llow). However, in-vitro proliferation (MLR) and IFNγ-production (ELISPOT) were markedly reduced with increasing age. Likewise, skin graft rejection was significantly delayed in older recipients and fewer graft infiltrating CD4+T-cells were observed. Old CD4+ T-cells demonstrated a significant impaired responsiveness as indicated by diminished proliferation and activation. In contrast, old alloantigen-specific CD4+CD25+FoxP3+ T-cells demonstrated a dose-dependent well-preserved suppressor function. Next, we examined characteristics of 18-month old alloreactive T-cells in a transgenic adoptive transfer model. Adoptively transferred old T-cells proliferated significantly less in response to antigen. Skin graft rejection was significantly delayed in older recipients, and graft infiltrating cells were reduced. In summary, advanced recipient age was associated with delayed acute rejection and impaired CD4+ T-cell function and proliferation while CD4+CD25+FoxP3+ T-cells (Tregs) showed a well-preserved function.

Defective CD8 Signaling Pathways Delay Rejection in Older Recipients.

Abstract CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8+ T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+CD44highCD62Llow effector/memory T cells and a reduced systemic IFN&ggr; production. When reconstituting young CBA Rag-1−/− mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2Kb T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFN&ggr; levels observed in old recipients had been linked to a compromised expression of the IL-2R &bgr; subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFN&ggr; production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8+ T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c+ cells. Collectively, our study demonstrated that aging delays allograft rejection. CD8+ T cells play a critical role in this process linked to a compromised production of IFN&ggr;, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8+ T cells and dendritic cells.

EFFECTOR/MEMORY T-CELL RESPONSE IS IMPAIRED IN ELDERLY RECIPIENTS AND LEADS TO DELAYED ACUTE ALLOGRAFT REJECTION: 1195

D.S. Bedi1, I.K. Kim2, C. Denecke3, X. Ge4, A. Jurisch4, G. Demirci5, X.C. Li6, S.G. Tullius4 1Division Of Transplant Surgery, Brigham and Women’s Hospital, Boston/MA/UNITED STATES OF AMERICA, 2Transplant Surgery Research Lab, Brigham and Women’s Hospital, Boston/MA/UNITED STATES OF AMERICA, 3Transplant Surgery Research Lab And Div. Of Transplantation, Brigham and Women’s Hospital, Boston, Boston/MA/UNITED STATES OF AMERICA, 4Division Of Transplant Surgery, Brigham and Women’s Hospital, Boston/UNITED STATES OF AMERICA, 5, Beth Israel Deaconess Medical Center, Boston/ UNITED STATES OF AMERICA, 6Transplant Research Center, Beth Israel Deaconess Medical Center, Boston/MA/UNITED STATES OF AMERICA

Age-dependent immune response after organ transplantation

Recipients older than 65 years represent the fastest growing patient group on the waiting list for organ transplantation. However, little is known about the consequences of the aging immune response on transplant outcome. Moreover an age dependent immune response may have important implications for an age adapted immunosuppression after transplantation. Thus, we investigated the age-dependent effector and regulatory T-cell response in an experimental murine transplant model.