The majority of kidney transplant recipients currently receive lymphodepleting (e.g., Thymoglobulin) or non-depleting (e.g., Basiliximab) antibodies at the time of transplantation. This form of therapy is known as induction and is employed as a means to prevent acute rejection and reduce maintenance immunosuppression (e.g., steroid avoidance or withdrawal). However, the salutary effects of induction are not observed in all patients and it remains uncertain whether induction therapy improves long-term allograft survival. These uncertainties stem from the fact that induction antibodies are double-edged swords: they deplete or block pathogenic lymphocytes but can also interfere with natural immunoregulatory mechanisms or lead to the rebound of alloreactive memory lymphocytes. Therefore, there is a critical need to characterize the immunological consequences of induction therapy and investigate how these changes relate to graft outcomes in humans. Towards these goals, we propose to perform ancillary, mechanistic studies on patients to be enrolled in an interventional trial comparing Basiliximab induction to Thymoglobulin induction in patients receiving identical maintenance immunosuppression (mycophenolic acid + Tacrolimus + early corticosteroid withdrawal).
The specific aims are to: (1) characterize the effects of lymphocyte-depletion (Thymoglobulin) vs. non-depleting targeting of the IL-2R1 chain (Basiliximab) on T and B cell subsets in living donor renal transplant recipients;and (2) investigate whether alterations in these cell populations correlate with acute rejection and early (1-yr) and late (3-yr) graft outcomes. We will test the hypothesis that changes in the distribution of memory and regulatory T and B cell subsets after induction are central to allograft outcome. We will also investigate the mechanisms by which these changes come about and how the T and B cell compartments influence each other. Innovative aspects of the study include the use of novel phenotypic and functional studies of B cell subsets after transplantation and characterizing T and B cell infiltrates in human kidney transplant biopsies using multiparametric immunofluorescence staining with quantum dot-conjugated antibodies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI096553-04
Application #
8685107
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Rice, Jeffrey S
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lakkis, Fadi G (2014) Immunology: TREG cells in transplantation-a double-edged sword? Nat Rev Nephrol 10:185-6
Macedo, Camila; Walters, John T; Orkis, Elizabeth A et al. (2012) Long-term effects of alemtuzumab on regulatory and memory T-cell subsets in kidney transplantation. Transplantation 93:813-21