Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents

NCT01678937 | Completed

• 1 other identifier: 1783-011
• Study Type: observational
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Liver Transplant Rejection; Immunosuppression

Keywords

Immunosuppression

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Secondary Outcomes (4)

• 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.

  Two weeks prior to conversion, Months 3 & 6 following conversion

• 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.

  Two weeks prior to conversion, Months 3 & 6 following conversion

• Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.

  Two weeks prior to conversion, Months 3 & 6 following conversion

• Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.

  Two weeks prior to conversion, Months 3 & 6 following conversion

Study Arms (3)

Control Group

Ten Healthy individuals will have blood drawn (4 green top tubes(40 ml = 8 tsp.)) at one time point at Northwestern for control purposes. Blood will be drawn to conduct the following tests: 1. 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). 2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and 3. HLA microchimerism \& HLA G.

Procedure: Blood Draw from Control Subjects

Monotherapy Group

Monotherapy patients \[cyclosporine (CyA) (10 patients), Tacrolimus (5 patients), mycophenolate mofetil (MMF) (10 patients), rapamycin (10 patients)\]: Blood will be drawn at one time point (4 green top tubes (40 ml = 8 tsp.)) to conduct the following tests: 1. 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). 2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and 3. HLA microchimerism \& HLA G.

Procedure: Blood Draw - CyA; Procedure: Blood Draw - Tacrolimus; Procedure: Blood Draw - MMF; Procedure: Blood Draw - Rapamycin

Conversion Group

Ten CNI monotherapy/dual therapy (CNI + MMF) patients pre-selected for conversion to rapamycin or wean to MMF monotherapy. Assays performed 2 weeks prior to conversion, 3-6 months following successful conversion. Liver function/drug levels monitored weekly during conversion until stable levels achieved. Patients converting from CNI monotherapy to rapamycin monotherapy (2-4 wks.): CNI discontinued when 2 therapeutic rapamycin levels (5-10) reached, graft function stable (clinical care protocol). MMF conversion: MMF dose slowly increased to 3 g/day (max.) while CNI therapy reduced by 1-2 mg/day (FK506) or 25-50 mg/day (CyA) monthly until CNI discontinued (1-6 months) (clinical care protocol). Monthly liver function/drug levels performed after successful conversion (standard of care).

Procedure: Blood Draw - Rapamycin

Interventions

Blood Draw - Rapamycin PROCEDURE

Ten calcineurin-inhibitors (CNI) monotherapy or dual therapy (CNI+MMF) patients will have blood taken (40 ml=8 tsp.) 2 wks. prior to conversion, 3-6 months post successful conversion. 1) Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2) Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers shown to induce regulatory T cells (ILT3; ILT4), 3) Soluble HLA G, and 4) Liver function/drug levels. If problems develop during conversion (e.g. acute rejection, significant drug side effects) requiring discontinuation of rapamycin, MMF and/or reversion to CNI therapy, assays will not be performed. Monthly liver function/drug levels performed after successful conversion (standard of care).

Also known as: Sirolimus

Conversion Group

Blood Draw from Control Subjects PROCEDURE

Ten healthy individuals will have blood drawn (40 ml = 8 teaspoons (tsps.)).Blood will be drawn at one time point for the following: * 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

Control Group

Blood Draw - CyA PROCEDURE

Blood drawn from 10 patients on cyclosporine (CyA) (40 ml = 8 tsp.)). Blood will be drawn at one time point for the following: * 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

Also known as: cyclosporine

Monotherapy Group

Blood Draw - Tacrolimus PROCEDURE

Blood drawn from 5 patients on Tacrolimus (40 ml = 8 tsp.) at one time point for the following: * 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

Also known as: Tacrolimus

Monotherapy Group

Blood Draw - MMF PROCEDURE

Blood will be drawn from 10 patients on mycophenolate mofetil (MMF) (40 ml or the equivalent of 8 teaspoons). Blood will be drawn at one time point for the following analysis: * 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

Also known as: mycophenolate mofetil

Monotherapy Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Liver transplant patients converting on stable IS monotherapy or undergoing conversion to rapamycin or MMF monotherapy.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead
• Northwestern Memorial Hospital: collaborator

Study Sites (1)

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Related Publications (21)

• Sayegh MH, Carpenter CB. Transplantation 50 years later--progress, challenges, and promises. N Engl J Med. 2004 Dec 23;351(26):2761-6. doi: 10.1056/NEJMon043418. No abstract available.

  PMID: 15616214 BACKGROUND

• 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. doi: 10.1097/00007890-200108150-00016.

  PMID: 11502975 BACKGROUND

• 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. doi: 10.1016/j.jhep.2005.11.047. Epub 2006 Jan 4.

  PMID: 16473433 BACKGROUND

• 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. doi: 10.1016/j.transproceed.2005.03.070.

  PMID: 15919439 BACKGROUND

• 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. doi: 10.1111/j.1399-3046.2004.00129.x.

  PMID: 15176965 BACKGROUND

• 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. doi: 10.1016/s0041-1345(02)02980-9. No abstract available.

  PMID: 12176465 BACKGROUND

• Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006 Aug;6(8):1774-80. doi: 10.1111/j.1600-6143.2006.01396.x.

  PMID: 16889539 BACKGROUND

• 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. doi: 10.1016/s0041-1345(96)00535-0. No abstract available.

  PMID: 9123261 BACKGROUND

• 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. doi: 10.1097/00007890-199701270-00012.

  PMID: 9020325 BACKGROUND

• 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. doi: 10.1002/lt.20872.

  PMID: 17004249 BACKGROUND

• 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. doi: 10.1034/j.1600-6143.2003.00109.x.

  PMID: 12780560 BACKGROUND

• 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. doi: 10.1002/hep.510280223.

  PMID: 9696010 BACKGROUND

• 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. doi: 10.1002/hep.510270406.

  PMID: 9537430 BACKGROUND

• 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. doi: 10.1002/1521-4141(200007)30:73.0.CO;2-N.

  PMID: 10940869 BACKGROUND

• 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. doi: 10.1097/01.tp.0000172217.97072.54.

  PMID: 16123728 BACKGROUND

• 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. doi: 10.2310/6650.2001.33789.

  PMID: 11523700 BACKGROUND

• Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. doi: 10.1182/blood-2004-10-3932. Epub 2005 Mar 3.

  PMID: 15746082 BACKGROUND

• 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.

  PMID: 16380475 BACKGROUND

• 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. doi: 10.4049/jimmunol.165.5.2374.

  PMID: 10946260 BACKGROUND

• 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. doi: 10.4049/jimmunol.167.4.1945.

  PMID: 11489974 BACKGROUND

• 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. doi: 10.1097/01.tp.0000194860.21533.b9.

  PMID: 16477233 BACKGROUND

Related Links

• PMID: 19141306

Biospecimen

Retention: SAMPLES WITH DNA

Blood tests: Monotherapy patients 1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2. 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). 3. Soluble HLA G Blood tests: Conversion patients 1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2. 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), 3. Soluble HLA G, and 4. Liver function and drug levels. Blood tests: Healthy controls (same tests as Monotherapy Group)

MeSH Terms

Interventions

Sirolimus; Cyclosporine; Tacrolimus; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Josh Levitsky, MD

  Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor in Medicine-Hepatology

Study Record Dates

• First Submitted: July 8, 2011
• First Posted: September 5, 2012
• Study Start: September 1, 2007
• Primary Completion: May 1, 2008
• Study Completion: September 1, 2008
• Last Updated: April 15, 2015

Record last verified: 2015-04

Locations

US (1)