Th1, Th2 and Monokine Responses as Risk Factors of Renal Transplant Rejection

Chronic transplant rejection remains the main cause of late kidney graft loss. We showed previously that patients with pretransplant CD4 helper defects and low in-vitro IL-10 responses demonstrated an extremely low risk of acute rejection and a significantly better 1- and 3-year graft function whereas pretransplant Th1 responses were not predictive (Weimer R et al. 1996 and 1998). In liver transplant recipients, we found CD4 helper function and in-vitro IL-10 responses significantly decreased compared to CsA-treated patients (Zipperle et al. 1997). If the same effect will be demonstrated in renal transplant recipients, Tacrolimus (Tacr) treatment might result in enhanced graft survival compared to CsA, when CD4 helper function and in-vitro IL-10 responses of the individual patient are elevated. Other studies of our group suggest a beneficial role of enhanced T-suppressor activity and of an IL-6 independent B cell/monocyte defect in the maintenance of long-term stable graft function, whereas enhanced monokine secretion (TNF-a, GM-CSF, IL-6) was found in chronic rejection (Weimer et al. 1990, 1992, 1994, 1998).

In the current randomized prospective study we will analyze the impact of CsA versus Tacr and of MMF versus azathioprine (Aza; 3 treatment groups: CsA/Aza, CsA/MMF and Tacr/Aza; steroid and prophylactic ATG treatment according to the Giessen protocol) on immune parameters and their predictive value regarding occurrence of acute and chronic rejection. As immune parameters we will assess CD4 helper function, in-vitro IL-4 and IL-10 responses of T cells and CD4+ T cells, respectively, in allogeneic cocultures of patient T cells with control B cells and in PHA-stimulated T cell cultures, T-cell dependent (PWM-stimulated allogeneic cocultures) and T-independent (SAC I-stimulated B cell cultures) immunoglobulin-secreting cell (ISC) responses, B-cell IL-6 and IL-10 responses and monokine responses (LPS-stimulated monocyte cultures) pretransplant, and 4 months, 1 year, 2 years and 5 years posttransplant. Serum cytokines and easily measurable parameters as neopterin, sIL-1RA and sCD30 will be assessed at the same time points. The same is true for flow cytometric analysis of cytokine receptor, adhesion molecule, costimulator molecule and surface molecule expression, respectively, which play an important role in cell-cell interactions and tolerance induction. Cytokine promoter gene polymorphisms will be determined to potentially enable pretransplant risk estimation. To establish a broadly available and rapid diagnostic method, we will compare the data of intracellular cytokine testing with the results of the much more difficult and time consuming coculture analyses used in our previous studies.

With a proposed follow-up of 5 years this prospective randomized study might enable a patient-tailored immunosuppressive therapy resulting in better graft function and prolonged graft survival by preventing chronic allograft rejection.

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Weimer R, Zipperle S, Daniel V, Pomer S, Staehler G, Opelz G. In vitro B cell response in long-term renal transplant recipients. Transplant Proc 1992; 24(6): 2537-2538

Weimer R, Zipperle S, Daniel V, Pomer S, Staehler G, Opelz G. IL-6 independent monocyte/B cell defect in renal transplant recipients with long-term stable graft function. Transplantation 1994; 57(1): 54-59

Weimer R, Zipperle S, Daniel V, Carl S, Staehler G, Opelz G. Pretransplant CD4 helper function and IL-10 response predict risk of acute kidney graft rejection. Transplantation 1996; 62(11): 1606-1614

Zipperle S, Weimer R, Golling M, Daniel V, Otto G, Opelz G. Impaired T cell IL-10 secretion and CD4 helper function in liver transplant patients treated with tacrolimus. Transplant Proc 1997; 29(1-2): 1079-1080

Weimer R, Zipperle S, Daniel V, Carl S, Staehler G, Opelz G. Superior 3-year kidney graft function in patients with impaired pretransplant Th2 responses. Transplant Int 1998; 11 (Suppl 1): 350-356