Abstract | Investigators

It is possible that tolerance induction may be occurring in a significant number of liver transplant recipients already as a result of variables intrinsic to the organ. In these individuals, tolerance was achieved either after abrupt discontinuation of immunosuppression, or following gradual weaning of immunosuppression long after transplantation. Importantly, the occurrence of rejection during weaning was reversed by reinstitution of immunosuppression, and did not result in a significant long-term damage to the graft. An existing ITN study (CF102) is set to identify immune and genetic profiles expressed in individuals undergoing weaning off immunosuppression, hoping to determine patterns and mechanisms that are associated with the development of tolerance.

To enhance tolerance, the study employs a lymphocyte depletion strategy with Campath-1H and gradual withdrawal from maintenance tacrolimus. Safeguards are set to assure appropriate
follow up of liver function. To obtain a “clean profile” the study excluded 60-70% of the candidates for liver transplantation (OLT) whose indication for transplantation is end-stage liver failure secondary to chronic active viral hepatitis C (CAHC) infection. The rationale for exclusion was the potential masking of immune and other characteristics expression of tolerance by an ongoing inflammatory and immune response against the hepatitis C (HCV).

The current proposal is focused on recipients undergoing OLT for CAHC. The aims are: 1. To determine whether HCV infected individuals who become tolerant express immune and genetic profiles that are similar to non-HCV infected recipients. 2. To examine whether the use of depletion strategy with Campath-1H affects early immune-mediated control of HCV infection, and if immunosuppression withdrawal at a later stage has favorable impact on the severity of HCV recurrence and injury to the transplanted graft. Participants in this study will include adult recipients whose indication for OLT is end-stage cirrhosis from CAHC. The recipients will be randomized to receive Campath-1H (Group I) vs. 3 months of steroids (group II), with Tacrolimus as maintenance monotherapy slowly withdrawn. Participants will be followed with liver function tests and liver biopsies obtained at predetermined intervals, or for the diagnosis of liver dysfunction.

The state of the alloimmune response and the presence of phenotypic profile of tolerance will be determined using assays that are described in the CF102 study, and the results will be correlated with the non-virally infected individuals. The impact of immunosuppression induction and withdrawal on HCV activity will be determined using the following variables:

1. 1. the incidence of severe fibrosing cholestatic hepatitis
2. 2. the development of graft fibrosis and cirrhosis
3. 3. the capacity to generate an effective T cell mediated anti-HCV response, and its affect on control of hepatitis and/or viral load.

These results, when correlated with CF102 study, will determine whether HCV infection affects the mechanism and/or expression of tolerance, and whether the means to augment and/or discontinue immunosuppression impacts on HCV recurrence and graft function.

Participating Investigators

	Chang, Kyong-Mi, University of Pennsylvania
	Turka, Laurence, University of Pennsylvania
	Hancock, Wayne, University of Pennsylvania
	Trotter, James, University of Colorado
	Wells, Andrew, University of Pennsylvania