Skip to Navigation
University of Pittsburgh
Print This Page Print this pages

January 7, 1999


Bioartificial liver system tested at UPMC

UPMC researchers have begun testing a new bioartificial liver assist system designed by Excorp Medical, Inc., that uses healthy liver cells from pigs to improve the liver function of critically ill patients with liver failure.

The trial will assess the safety of the system, but researchers also will pay close attention to whether it can improve a patient's condition until transplantation is feasible or if it can obviate the need for transplantation if the failing liver recovers .

"One patient has already undergone treatment without any harmful effects. This patient had multiple serious medical complications associated with liver failure as well as her underlying disease. She tolerated the treatment well, and by clinical measures, her neurological status initially improved. Unfortunately, as is often the case with these patients, she suffered a serious setback a week later and died from an overwhelming infection," said George Mazariegos, assistant professor of surgery at the Thomas E. Starzl Transplantation Institute and co-director of the liver transplant intensive care (ICU) service at 'UPMC Presbyterian. Mazariegos is also co-principal investigator of the study.

"Because this is a Phase I clinical trial, we are most concerned about the safety of the system. But we'll be looking at efficacy as well. The system may benefit patients if their condition improves and they can be considered eligible for transplantation or if their liver regenerates and resumes normal function," said David J. Kramer, co-principal investigator, associate professor of anesthesiology and critical care medicine and co-director of the liver transplant ICUs with Mazariegos.

Researchers intend to study 15 patients with encephalopathy, a life-threatening complication of both chronic and acute liver failure. Because the liver is unable to function properly, toxins normally cleansed by the liver circulate in the bloodstream and to the brain. In its severest form, patients become unresponsive or comatose. Encephalopathy is one of the most common reasons liver disease patients are admitted to the intensive care unit. Chronic liver failure occurs in patients who develop cirrhosis after many years with liver disease. Acute liver failure, also known as fulminant hepatic failure, is a more sudden assault on the liver, occurring in patients with no prior history of liver d isease. These may be patients who have been poisoned by mushrooms or toxic levels of acetaminophen, or who suddenly contract a virus that attacks their liver.

For most patients with liver failure, the only treatment is liver transplantation. But not all patients are medically stable enough to be considered as candidates. And a shortage of organs means that many who are listed die without the opportunity to unde rgo a transplant. In a small percentage of cases, patients with acute liver failure can recover and do not need transplants.

Researchers will compare the outcomes of patients who receive treatments with the Excorp Medical bioartificial liver system, which takes 12 hours and may be repeated, with similar patients who receive standard intensive care treatment.

A catheter connects a patient to the system, which remains outside the body, and treats blood that passes through a cylinder filled with hollow polymer fibers and a suspension containing billions of pig liver cells. The fibers act as a barrier to prevent proteins and cell byproducts of the pig cells from coming in direct contact with the patient's blood but allow the necessary contact between the cells so that toxins in the blood can be removed. "There are, as yet, no proven bioartificial therapies to treat patients with encephalopathy and liver failure. We are hopeful that careful and measured research using this system will offer some hope to the 10,000 patients waiting for liver transplants," said Daniel G. Miller, president and CEO of Excorp Medical.

Review by the U.S. Food and Drug Administration was necessary to assure the study uses the proper mechanisms to screen and monitor for potential animal viruses. Like all studies involving humans, the study was also reviewed and approved by Pitt's Institut ional Review Board.


GSPH awarded $5.8 million to develop new HIV therapies

A team of researchers at Pitt's Graduate School of Public Health (GSPH) has been awarded a federal grant of $5.8 million over four years to develop and study new HIV therapies based on dendritic cells.

"We've been working for several years with dendritic cells. They turn on T-cells against invading pathogens. In this study, we expect to engineer the dendritic cells in such a way as to be able to manipulate them, to turn them on against HIV and increase T-cell immunity," said Charles Rinaldo Jr., chairman and professor of infectious diseases and microbiology and professor of pathology at GSPH.

"Highly active anti-retroviral treatments have been used for several years with striking impact. Commonly known as triple-drug therapies, these drug combinations reduce viral loads (the current best measure of severity of HIV infection), but they don't he lp the immune system to withstand a reinfection or a recurrence of virus hidden in the body. Our work with dendritic cells may equip us with a one-two punch that will cure the disease," he added.

Dendritic cells are specialized white blood cells that normally comprise only 1 percent of circulating blood. They have an important purpose in the body's immune response and are often described as the "pacemaker" of the immune system. As with other white blood cells, dendritic cells "eat" antigens, the molecular tags found on all substances foreign to the body, including HIV. Dendritic cells, however, present pieces (flags) of antigen on their outer surface then travel to the lymph nodes in the body wher e T-cells are manufactured.

The dendritic cells effectively communicate to the T-cells: "This is what the enemy looks like. Seek and destroy anything that looks like this." The T-cells then trigger a complex immune response, which includes growing more T-cells that can specifically seek out and destroy antigen flags on HIV identical to those presented by the dendritic cells.

Led by Rinaldo, the multi-disciplinary team is comprised of five investigators. Simon Barratt-Boyes, assistant professor of infectious diseases and microbiology, is studying how dendritic cells can be manipulated as vaccines in a monkey, simian immunodefi ciency virus (SIV), model of HIV. Louis Falo, assistant professor and vice chairperson of the dermatology department, is developing a DNA-based vaccine. He uses a gene "gun" to shoot gene-coated gold particles directly into dendritic cells in the skin. Ta rgeted dendritic cells become factories that produce HIV antigen flags used to teach killer T-cells how to recognize and destroy HIV-infected cells.

Albert Donnenberg, associate professor of medicine, is refining the direct measurement of T-cell turnover in HIV infection following pharmacological and therapeutic intervention. Cara Wilson, assistant professor of infectious diseases and clinical immunol ogy at the University of Colorado, will look at the role of cytokines, which are hormone-like substances, in enhancing T-cell function in dendritic cell therapy for HIV. Michael Lotze, professor of surgery and of molecular genetics and biochemistry and co -director of the University of Pittsburgh Cancer Institute's biological therapeutics program, will soon begin a pilot clinical study of dendritic cell gene therapy for HIV.


Clues to transplant tolerance linked to immunity cell

The process by which the human immune system takes little notice of certain infections is similar to the way it takes little notice of a transplanted organ under the most perfect immunological conditions, say two authors, one a Nobel laureate and the othe r the "father of transplantation," in a recent issue of the New England Journal of Medicine.

Thomas E. Starzl, professor of surgery and director, University of Pittsburgh Thomas E. Starzl Transplantation Institute, and Rolf M. Zinkernagel, professor of pathology and director, Institute for Experimental Immunology, University of Zurich, report tha t the mechanisms by which certain micro-organisms can exist in the human host closely resemble the mechanisms that confer permanent acceptance of a transplanted organ.

The fact that antigens ã foreign substances like those in micro-organisms and cells from a donor organ ã migrate through the body to take up residence in various tissues is the common thread that explains how the body's immune system responds to both infe ctious diseases and organ transplants. The authors say this mechanism, involving a delicate balancing act, governs the immune system's response or nonresponse against infections, tumors and transplanted organs from either human or animal donors.

"Although the relation between infection and transplantation immunity is complicateda the mechanisms and rules are basically the same," the authors write. The article is a convergence of theories from two separate medical specialties and draws upon the se minal works of Starzl and Zinkernagel.

In a 1992 Lancet article, Starzl observed that chimerism ã the coexistence of donor and recipient immune cells ã was present in transplant recipients who had survived with their transplanted organs for up to 29 years.

In addition, recipient immune system cells were found in the transplanted donor organs. The discovery gave way to the belief that chimerism is a prerequisite for, but not synonymous with, long-term acceptance. It also confirmed that a transplant operation not only serves to replace organ function but it introduces as well a small piece of the donor's immune system into the recipient.

In their New England Journal of Medicine article, Starzl, who performed the world's first liver transplant in 1963, and Zinkernagel, who shared the 1996 Nobel Prize in medicine for discoveries related to how the immune system recognizes virus-infected cel ls, elaborate on the process necessary for transplant tolerance. How the immune system defends itself against noncytopathic micro-organisms, which employs complex cell-mediated responses, provides the strongest parallels to transplant immunology. Noncytopathic micro-organisms, including those that cause tuberculosis, hepatitis, herpes and warts, are less virulent than the cytopathic variety, like the bacteria for pneumonia, and they often can be accommodated by the host so that the two coexist. For instance, in some phases of the disease process of infection, noncytopathic antigens can be "noninjurious," as when a person carries hepatitis but has no symptoms. Such is the case with a stable organ transplant recipient whose immune system has accepte d the graft.

Some noncytopathic micro-organisms ã such as warts ã eventually draw little or no attention to themselves; they are essentially ignored by an immune system that is "indifferent" to their presence in nonlymphoid tissues. Successful long-term organ acceptan ce could be achieved under the same immunological conditions.

"In time, a stable allograft [organ from a human donor] from this process may come to resemble a wart that never really induces an immune response nor is readily reached by immune effector mechanisms," the authors say.

Elaborating on their work, the authors identify four closely linked steps required for completely successful organ engraftment. The process begins once the donor leukocytes travel to recipient lymphoid tissues. Here, the donor cells induce the recipient a nti-graft T cells in an immunological war game. Both types of cells ã the T cells of the recipient that react against the donor and the donor T cells that react against the recipient ã are left exhausted. No longer effective, they cancel each other out. T hese steps are called clonal exhaustion/deletion of the recipient response and clonal exhaustion/deletion of the donor-leukocyte response.

The third step required is to maintain this neutral status of clonal exhaustion. Finally, in order to sustain acceptance of the transplanted organ, the donor organ must remain nearly depleted of its donor immune system cells, which are replaced with like- recipient cells.

Leave a Reply