New Renal Transplant Registry Targets Immune Tolerance

Jeffrey B. Matthews, PhD

Disclosures

July 29, 2004

Transplant tolerance has been the ultimate goal of transplant surgeons, physicians, and scientists since it was first demonstrated experimentally 50 years ago. In the past 2 decades, progress has intensified such that regimens designed to produce tolerance are now being clinically evaluated in humans. Although the definition of tolerance appears to be a moving target, clinically it can be defined as the lack of an immune response to the foreign antigens expressed by an organ allograft in the absence of ongoing immunosuppressive therapy. This functional definition therefore precludes the use of long-term immunosuppression and would necessitate withdrawal of immunosuppression to properly determine whether tolerance has been achieved.

To date, liver transplantation has been the most successful setting for immunosuppressive drug withdrawal. Generally, liver transplant recipients require less immunosuppression than recipients of other solid organ allografts such as hearts or kidneys,[1] and many rejection episodes are self-limiting and do not require additional high-dose immunosuppression.[2,3] Weaning of immunosuppression is also a uniquely safer proposition in liver transplant recipients, as the liver's regenerative capacity allows it to tolerate acute immunologic insult, perhaps explaining the clinical observation that an episode of acute rejection does not necessarily alter long-term liver graft survival.[4,5] However, such is not the case in other types of solid organ transplantation, in particular renal transplantation, where the deleterious effects of acute rejection on allograft function and survival are well documented.[6]

In renal transplantation, therefore, investigators seeking to clinically test new tolerance strategies find themselves in a catch-22: in order to effectively evaluate a given tolerogenic protocol that aims to increase the safety of transplantation, the same patients must be exposed to the significant risk of precipitating acute rejection. Although slow weaning and intense monitoring of those being withdrawn from immunosuppression can minimize these risks, the situation is complicated by the fact that there currently exist no reliable biomarkers indicative of tolerance. Until such biomarkers are identified and validated, clinical end points of tolerance are limited to a "lack of rejection" and immunosuppression withdrawal will continue to be a risky proposition requiring great care on the part of both the patient and the physician.

In order to address the lack of clinical end points of tolerance, the Immune Tolerance Network (ITN) has established the "ITN Registry of Tolerant Kidney Transplant Patients," a multi-institutional collaboration aiming to identify and study a rare group of renal transplant recipients who have already discontinued immunosuppressive therapy, but have so far not rejected their grafts.

Emory University's Kenneth Newell, the principal investigator of the study, believes that a retrospective approach such as this has inherent advantages over drug withdrawal studies that go beyond simply the avoidance of empiric withdrawal of immunosuppression.

"It is certainly a much safer approach, but it also may be a more relevant approach," says Newell. "Some of these patients may have been off all immunosuppressives for several years and so the assays we perform may reflect conditions associated with the persistence of tolerance, rather than the development of short-term and, quite possibly, fleeting tolerance."

Another key element of the study, according to Newell, is the choice of control groups that can be compared with the tolerant phenotype. Several patient cohorts will be studied in parallel, including: (1) kidney transplant recipients off all immunosuppressive drugs with normal allograft function, (2) recipients off all immunosuppressive drugs with slowly declining or mildly impaired function believed not to be the result of rejection (ie, recurrent disease, drug toxicity), (3) recipients on minimal immunosuppression (ie, prednisone 10 mg/day), (4) recipients maintained on standard immunosuppressive therapy with normal allograft function, (5) recipients maintained on standard immunosuppressive therapy with impaired or declining allograft function, and (6) recipients of kidneys from identical twin donors. In addition, when possible, donors will also be approached to participate.

Taking advantage of the ITN's extensive network of standardized assay facilities, the initial investigations will involve a battery of cellular, genetic, and immunologic parameters measured over a 2-year period. Assays include cytokine snapshots, HLA-genotype, analysis of gene polymorphisms for selected genes that regulate immune function, gene expression, T-cell receptor diversity, trans-vivo delayed-type hypersensitivity, and detection of T-cell responsiveness to donor antigens by ELISPOT. The longitudinal aspects of the study – following patients over several visits – may also help investigators develop biomarkers indicative of the loss of tolerance or that provide an early warning for subsequent rejection episodes. Once initial investigations are complete, it is the intent of the investigators that the registry becomes a new resource for the entire transplant community.

First, however, Newell and colleagues from the University of Wisconsin, the National Institutes of Health, Imperial College in London, INSERM in Nantes, France, and the Swedish Medical Center in Seattle, Washington, are now reaching out to transplant physicians around the world in order to identify enough tolerant patients to meet their goal of 50 patient registrants. "We know, anecdotally, that these patients are out there," says Newell. "However, it is a rare group of patients and in many cases there may be no records that they even exist. So we need help from the community if we are to succeed."

Such patients may exist for a variety of reasons, including patient noncompliance or extreme side effects or other complications that warrant discontinuation of immunosuppression. Physicians, transplant coordinators, nurses, or other individuals who believe they know of renal transplant recipients who may be eligible for this study are asked to contact Dr. Newell for more information at registry@immunetolerance.org or toll-free at 1-866-752-6245. Study eligibility criteria are listed in the Table . Further information on the registry project may be found at www.immunetolerance.org/registry.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....