Renal Failure, Chronic Clinical Trial
Official title:
Role of Th1, Th2 and Monokine Responses as Risk Factors of Acute and Chronic Renal Transplant Rejection – Impact of Different Immunosuppressive Protocols
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 on Th1, Th2 and monokine responses and their predictive value
regarding occurrence of acute and chronic rejection. With a proposed follow-up of 5 years
this study might enable a patient-tailored immunosuppressive therapy resulting in prolonged
graft survival.
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.
Weimer R, Pomer S, Staehler G, Opelz G. Increased T suppressor activity in renal transplant
recipients with long-term stable graft function. Clinical Transplantation 1990; 4: 280-286
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
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