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

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00150891
• Other study ID #: NTx-prosp-001
• Status: Completed
• Phase: N/A
• First received: September 6, 2005
• Last updated: May 8, 2007
• Start date: January 1998
• Est. completion date: January 2006

Study information

• Verified date: May 2007
• Source: University of Giessen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Observational

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 84
• Est. completion date: January 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 14 Years and older

Eligibility

Inclusion Criteria:

• Renal transplant recipients in the Giessen renal transplant unit

Exclusion Criteria:

• Contraindications against blood-taking (anemia with hemoglobin<9.5 g/l, hypotension etc.)

• No informed consent by the patient

Study Design

Observational Model: Defined Population, Primary Purpose: Screening, Time Perspective: Longitudinal

Related Conditions & MeSH terms

• Kidney Failure, Chronic
• Renal Failure, Chronic

Intervention

Procedure:
• Kidney transplantation

Drug:
• cyclosporine A

• tacrolimus

• azathioprine

• mycophenolate mofetil

Locations

Country	Name	City	State
Germany	Department of Internal Medicine, University of Giessen	Giessen

Sponsors (7)

Lead Sponsor	Collaborator
University of Giessen	Astellas Pharma Inc, Biotest, Fresenius AG, Heidelberg University, Hoffmann-La Roche, Novartis

Country where clinical trial is conducted

Germany, 

References & Publications (10)

Weimer R, Melk A, Daniel V, Friemann S, Padberg W, Opelz G. Switch from cyclosporine A to tacrolimus in renal transplant recipients: impact on Th1, Th2, and monokine responses. Hum Immunol. 2000 Sep;61(9):884-97. — View Citation

Weimer R, Mytilineos J, Feustel A, Preiss A, Daniel V, Grimm H, Wiesel M, Opelz G. Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients. Transplantation. 2003 Jun 27;75(12):2090-9. — View Citation

Weimer R, Staak A, Süsal C, Streller S, Yildiz S, Pelzl S, Renner F, Dietrich H, Daniel V, Rainer L, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. ATG induction therapy: long-term effects on Th1 but not on Th2 responses. Transpl Int. 2005 Feb;18(2):226-36. — View Citation

Weimer R, Streller S, Staak A, Heilke M, Li D, Dietrich H, Daniel V, Feustel A, Rainer L, Zinn S, Friemann S, Ernst W, Grimm H, Padberg W, Zimmermann T, Opelz G. Effects of three immunosuppressive regimens on CD4 helper function, B cell monocyte and cytok — View Citation

Weimer R, Süsal C, Yildiz S, Staak A, Pelzl S, Renner F, Dietrich H, Daniel V, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of different immunosuppressive regimens. — View Citation

Weimer R, Süsal C, Yildiz S, Streller S, Pelzl S, Staak A, Renner F, Dietrich H, Daniel V, Feuring E, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. sCD30 and neopterin as risk factors of chronic renal transplant rejection: impact of cyclosporine A, tacroli — View Citation

Weimer R, Zipperle S, Daniel V, Carl S, Staehler G, Opelz G. Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection. Transplantation. 1996 Dec 15;62(11):1606-14. — View Citation

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. Transpl Int. 1998;11 Suppl 1:S350-6. — View Citation

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 Jan;57(1):54-9. — View Citation

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 Feb-Mar;29(1-2):1079-80. — View Citation