Immune Tolerance in Transplantation

Each year, nearly 29,000 organ transplants are performed in the United States. For all of these people, anti-rejection therapies known as "immunosuppressive drugs" are a lifeline that prevents their body from rejecting the transplant. A number of immunosuppressive medications are available that have proven quite successful at preventing rejection over the short term. However, these drugs work by suppressing all of the immune system - even the parts that protect from real threats. This means that people taking immunosuppressive drugs are at risk of developing serious infections, and sometimes even cancer. Additionally, immunosuppressive drugs only work for as long as a patient is taking them. Once a patient stops, they are at risk of rejecting the transplant.

The Immune Tolerance Network (ITN) is working to find new, more specific immune tolerance therapies. These therapies are medications and techniques that are designed to reprogram the immune system so that it learns to tolerate the presence of a transplanted organ or tissue, but leaves the disease-fighting parts to continue their good work. These therapies would ideally be short-term, meaning that they don't need to be taken every day for life, but would still have a lasting effect against transplant rejection.

Research Focus - Transplantation

The ITN conducts solid organ transplant studies with two complementary goals. The primary goal of our interventional studies is to achieve the complete and planned withdrawal of all immunosuppression while maintaining the healthy function of the graft organ. The ITN is also looking for biomarkers of tolerance that would be useful in predicting when transplant patients can be weaned from immune suppressive drugs. By continuing registry studies of operationally tolerant kidney transplant patients, the ITN aims to validate previously identified biomarker signatures as well as better understand the mechanisms of tolerance. In addition, immunosuppression-tapering studies in liver transplant recipients have enabled drug-free allograft survival among a number of patients and the ITN will build on these studies to identify biomarkers of tolerance in similar cohorts of patients.

The ITN also conducts novel interventional studies to actively guide the immune system towards acceptance and tolerance of a transplanted organ. Previous ITN trials demonstrated that induction of transient chimerism (the simultaneous presence of donor and recipient immune systems) via combined bone marrow and kidney transplant can achieve operational tolerance in some individuals. Building on this success, the ITN is pursuing new approaches that combine therapeutic cell transfers with solid organ transplantation to create an immunological environment that facilitates tolerance.

Clinical Trials - Transplantation

Active

Post-transplant Cyclophosphamide (ACCEPTOR)

Principal Investigator:
Lode Swinnen, Johns Hopkins Hospital, Baltimore, MD

Ephraim Fuchs, Johns Hopkins Hospital, Baltimore, MD

Robert Montgomery, Johns Hopkins Hospital, Baltimore, MD

This trial is a phase II, single arm, open-label, single center study to assess the ability of a specialized pre-transplant conditioning regimen, bone marrow transplantation and high dose post-transplant cyclophosphamide to induce tolerance and enable long-term discontinuation of immunosuppression in six kidney transplant recipients.

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Immunosuppressive Medications for Participants in ITN005CT (EXIIST)

Principal Investigator:
Daniel C. Brennan, MD, Washington University, St. Louis, MO

This study is for participants who have received up to three islet cell infusions as a previous participant in the ITN005CT study. Study participants will receive a maintenance immunosuppressive treatment regimen consisting of a combination of orally administered drugs (tacrolimus (Prograf®), sirolimus (Rapamune®), mycophenolate mofetil (MMF, Cellcept®), and/or mycophenolic acid (MPA, Myfortic®).) This protocol provides a way to supply these immunosuppressive medications to subjects whose islets continue to function and make C-peptide.

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Research Study of ATG and Rituximab in Renal Transplantation (RESTARRT)

Principal Investigator:
James Markmann, MD, Massachusetts General Hospital

The purpose of the RESTARRT study is see if a combination of two drugs, (ATG and rituximab), given at the time of the transplant surgery, will help reduce or eliminate the need for long-term immunosuppressive medication.

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Mixed Chimerism II: Renal Allograft Tolerance through Mixed Chimerism

Principal Investigator:
David H. Sachs, MD, Harvard Medical School

This study will examine the safety and effectiveness of a combination kidney and bone marrow transplant from a relative with the same (or nearly the same) blood cell type as the transplant recipient. An investigational medication will be given prior to and after the transplant to help protect the transplanted kidney from attack by the body's immune system.

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Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients (WISP-R)

Principal Investigator:
Sandy Feng, University of California San Francisco, San Francisco, CA

Antirejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent their bodies from rejecting the new organ. Long-term use of these drugs places transplant recipients at higher risk of serious infections and certain types of cancer. The purpose of this study is to determine whether immunosuppressive drugs can be safely withdrawn over a minimum of 9 months from children who received liver transplants at least 4 years ago.

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Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (A-WISH)

Principal Investigator:
Abraham Shaked, University of Pennsylvania, Philidelphia, PA

In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications. However, these medications can cause long-term side effects, such as infection, kidney problems, diabetes and cancer. This study is investigating whether liver transplant recipients can slowly be taken off these drugs under medical supervision.

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Completed

Associating Renal Transplantation With the ITN Signature of Tolerance (ARTIST)

Principal Investigator:
Kenneth Newell, Emory University, Atlanta, GA

Laurence Turka, Harvard Medical School, Boston, MA

Anil Chandraker, Harvard Medical School, Boston, MA

This is an observational study for people who have received a kidney transplant within the past 1 to 5 years. Researchers in this study are looking for a certain pattern of genes and cells in the blood that has been found in a group of rare transplant patients who do not need immunosuppression.

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A Screening Study for Identification of Tolerance Markers in Liver Transplant Recipients Who Received Campath-1H Immunosuppression

Principal Investigator:
Andreas Tzakis, MD, Jackson Memorial Hospital, Miami, FL

Panagiotis Tryphonopoulos, MD, University of Miami, Miami, FL

This study aims to identify which study participants - all of whom previously received a liver transplant under Campath-1H immunosuppression - exhibit specific tolerogenic genotypes. Our hypothesis is that patients who exhibit these genotypes might be good candidates for future immunosuppression withdrawal.

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Study of Tolerant Kidney Transplant Recipients (FACTOR)

Principal Investigator:
Kenneth Newell, Emory University

Immunosuppressive drugs are all that separate transplant recipients from rejecting their transplanted organs. The ITN Registry of Tolerant Kidney Transplant Recipients is searching for those rare kidney transplant recipients who have stopped their immunosuppression, but for some reason have not rejected their transplants. If you have received a kidney transplant and have been off all immunosuppressive medications for 1 year and have good kidney function, or if you received your kidney from an identical twin, you may be eligible to participate.

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Immune System Suppression with Alemtuzumab and Tacrolimus in Liver Transplantation Patients (TILT)

Principal Investigator:
J. Richard Thistlethwaite, University of Chicago, Chicago, IL

This study will determine whether treatment with alemtuzumab and tacrolimus is effective in preventing organ rejection and maintaining the recipient's health after liver transplantation in patients with end-stage liver disease, and whether gradual tapering of tacrolimus treatment is safe for these patients.

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Pilot Study Using Donor Stem Cells and Campath-1H to Induce Renal Transplant Tolerance

Principal Investigator:
George W. Burke, University of Miami, Miami, FL

Alemtuzumab is a man-made antibody used to treat certain blood disorders. This study will evaluate treatment of kidney transplant recipients with alemtuzumab and other immune system suppressing medications with or without infusions of bone marrow stem cells from the kidney donor. The purpose of this study is to find out which strategy is more effective in preventing organ rejection and maintaining patient health.

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Belatacept to Prevent Organ Rejection in Kidney Transplant Patients

Principal Investigator:
Flavio Vincenti, University of California, San Francisco, CA

Christian Larsen, MD, Emory University, Atlanta, GA

Belatacept is an experimental medication shown in clinical trials to have immune system suppression properties in people who have had kidney transplants. This study will determine whether a combination of anti-rejection drugs, including belatacept, can prevent the rejection of a first-time, non-HLA identical kidney transplant and allow patients to be safely withdrawn from anti-rejection therapy one year post-transplant.

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Campath-1H/Tacrolimus/Sirolimus Withdrawal in Renal Transplantation

Principal Investigator:
Stuart Knechtle, University of Wisconsin, Madison, WI

The purpose of this study is to test the safety and effectiveness of using alemtuzumab in combination with two other drugs, sirolimus and tacrolimus, to prevent organ rejection after kidney transplantation. This study will also test whether this combination of medications will allow patients to eventually stop taking antirejection medications entirely.

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Mixed Chimerism and Renal Allograft with Non-Myeloablative Conditioning in Patients with ESRD Due to Multiple Myeloma

Principal Investigator:
Megan Sykes, Massachusetts General Hospital, Boston, MA

The purpose of this study is to determine whether a combined bone marrow and kidney transplant will be effective in treating stage II or greater multiple myeloma and associated kidney failure. This study will determine whether transplant rejection and the need for immunosuppressive drugs are decreased with this combined transplant approach.

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Mixed Chimerism I: Renal Allograft Tolerance Through Mixed Chimerism

Principal Investigator:
David H. Sachs, Massachusetts General Hospital, Boston, MA

A. Benedict Cosimi, Massachusetts General Hospital, Boston, MA

This study examines the safety and effectiveness of a combination kidney and bone marrow transplant from a relative with the same (or nearly the same) blood cell type as the transplant recipient. An investigational medication will be given prior to and after the transplant to help protect the transplanted kidney from attack by the body's immune system.

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Multicenter Trial of Islet Transplantation in Type 1 Diabetic Patients Using the Edmonton Protocol

Principal Investigator:
James Shapiro, University of Alberta, Edmonton, Alberta , Canada

This was a multicenter clinical trial of the Edmonton protocol for islet transplantation.

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