Immunosuppression Clinical Trial
Official title:
Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents
Verified date | April 2015 |
Source | Northwestern University |
Contact | n/a |
Is FDA regulated | No |
Health authority | United States: Institutional Review Board |
Study type | Observational |
This study is being done with the purpose of trying to understand if and why transplant recipients may develop tolerance to their transplanted organ. Tolerance means being able to lower or take away immunosuppression (anti-rejection medications) without causing organ rejection.
Status | Completed |
Enrollment | 31 |
Est. completion date | September 2008 |
Est. primary completion date | May 2008 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
Inclusion Criteria: - Age =18 years - Orthotopic or Living-Related liver transplant (LT) recipient - Monotherapy patients: > 6 months with stable graft function on current monotherapy (CNI, MMF, or rapamycin) - Converting patients: CNI therapy converting to rapamycin or MMF monotherapy and > 6 months of stable graft function. - >1 years post-LT without an acute rejection episode or chronic rejection - Normal liver function tests (no recurrent HCV, chronic rejection, autoimmune hepatitis, etc.) - No history of induction or lymphocyte depletion therapy Exclusion Criteria: - Multi-visceral organ recipients - Graft dysfunction of any etiology - Inadequate follow-up or available outcomes - Unable to understand, sign or ask questions regarding the informed consent process and protocol |
Observational Model: Case Control, Time Perspective: Prospective
Country | Name | City | State |
---|---|---|---|
United States | Northwestern Memorial Hospital | Chicago | Illinois |
Lead Sponsor | Collaborator |
---|---|
Northwestern University | Northwestern Memorial Hospital |
United States,
Battaglia M, Stabilini A, Draghici E, Gregori S, Mocchetti C, Bonifacio E, Roncarolo MG. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes. 2006 Jan;55(1):40-9. — View Citation
Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. Epub 2005 Mar 3. — View Citation
Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, Williams R. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology. 1998 Apr;27(4):926-33. — View Citation
Donckier V, Troisi R, Le Moine A, Toungouz M, Ricciardi S, Colle I, Van Vlierberghe H, Craciun L, Libin M, Praet M, Noens L, Stordeur P, Andrien M, Lambermont M, Gelin M, Bourgeois N, Adler M, de Hemptinne B, Goldman M. Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion. Liver Transpl. 2006 Oct;12(10):1523-8. — View Citation
Girlanda R, Rela M, Williams R, O'Grady JG, Heaton ND. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc. 2005 May;37(4):1708-9. — View Citation
Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001 Aug 15;167(4):1945-53. — View Citation
Hurwitz M, Desai DM, Cox KL, Berquist WE, Esquivel CO, Millan MT. Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation. Pediatr Transplant. 2004 Jun;8(3):267-72. — View Citation
Koenen HJ, Fasse E, Joosten I. Cyclosporine preserves the anergic state of human T cells induced by costimulation blockade in vitro. Transplantation. 2005 Aug 27;80(4):522-9. — View Citation
Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006 Aug;6(8):1774-80. Review. — View Citation
Mazariegos GV, Reyes J, Marino I, Flynn B, Fung JJ, Starzl TE. Risks and benefits of weaning immunosuppression in liver transplant recipients: long-term follow-up. Transplant Proc. 1997 Feb-Mar;29(1-2):1174-7. — View Citation
Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, McMichael J, Fung JJ, Starzl TE. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997 Jan 27;63(2):243-9. — View Citation
Mazariegos GV, Zahorchak AF, Reyes J, Ostrowski L, Flynn B, Zeevi A, Thomson AW. Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am J Transplant. 2003 Jun;3(6):689-96. — View Citation
Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol. 2000 Sep 1;165(5):2374-81. — View Citation
Nikolaeva N, Bemelman FJ, Yong SL, van Lier RA, ten Berge IJ. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation. 2006 Feb 15;81(3):445-54. — View Citation
Oike F, Yokoi A, Nishimura E, Ogura Y, Fujimoto Y, Kasahara M, Kaihara S, Kiuchi T, Egawa H, Uemoto S, Tanaka K. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc. 2002 Aug;34(5):1521. — View Citation
Sayegh MH, Carpenter CB. Transplantation 50 years later--progress, challenges, and promises. N Engl J Med. 2004 Dec 23;351(26):2761-6. — View Citation
Szabo G, Gavala C, Mandrekar P. Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. J Investig Med. 2001 Sep;49(5):442-9. — View Citation
Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, Hayashi M, Kanematsu T, Tanaka K. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001 Aug 15;72(3):449-54. — View Citation
Tisone G, Orlando G, Cardillo A, Palmieri G, Manzia TM, Baiocchi L, Lionetti R, Anselmo A, Toti L, Angelico M. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. J Hepatol. 2006 Apr;44(4):702-9. Epub 2006 Jan 4. — View Citation
Woltman AM, de Fijter JW, Kamerling SW, Paul LC, Daha MR, van Kooten C. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur J Immunol. 2000 Jul;30(7):1807-12. — View Citation
Wong T, Nouri-Aria KT, Devlin J, Portmann B, Williams R. Tolerance and latent cellular rejection in long-term liver transplant recipients. Hepatology. 1998 Aug;28(2):443-9. — View Citation
* Note: There are 21 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Track interval outcome measures for development of higher percentages of FOXP3+ T1 regulatory cells in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy. | Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4). Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells). Liver function and drug levels. |
Two weeks prior to conversion, Months 3 & 6 following conversion | No |
Primary | Track interval outcome measures for development of higher percentages of FOXP3+ T regulatory cells in liver transplant recipients after conversion from CNI to rapamycin comparing to MMF monotherapy. | Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4). Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells). |
Two weeks prior to conversion, Months 3 & 6 following conversion | No |
Secondary | Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy. | Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4). Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells). HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G) Liver function and drug levels. |
Two weeks prior to conversion, Months 3 & 6 following conversion | No |
Secondary | Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in liver transplant recipients after conversion from CNI to rapamycin or MMF monotherapy. | Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4). Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells). HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G)(hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy) |
Two weeks prior to conversion, Months 3 & 6 following conversion | No |
Secondary | Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points. | CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points. | Two weeks prior to conversion, Months 3 & 6 following conversion | Yes |
Secondary | Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points. | Document Rapamycin side effects - oral ulcers, edema, pancytopenia, gastrointestinal dysfunction; or MMF side effects - pancytopenia, gastrointestinal dysfunction. Review liver function and drug levels at designated time points. | Two weeks prior to conversion, Months 3 & 6 following conversion | Yes |
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