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New Anti-Rejection Studies Meet with Success

Most complex immune responses, like those we all rely upon to kill cancer cells or cells damaged by an infecting virus, are directed by a special kind of white blood cell called the T lymphocyte or the T cell.It is this same class of white blood cells that is lost in individuals infected with HIV. Indeed, for the AIDS patient, it is the loss of normal T lymphocyte numbers that underlies their susceptibility to otherwise harmless infectious agents. Likewise the recipient of a transplanted tissue or organ faces a higher susceptibility to infectious agents, albeit the impairment is no where near that faced by AIDS patients, because a transplant recipient’s immune system is impaired by the medicines required to prevent the rejection of the life saving graft. In addition, nearly all patients taking anti-rejection medications dream of the day they can decrease their dependence on the drugs because the drugs are expensive, difficult to take, and have other side effects.

For the past 30 years, immunologists have studied the T lymphocyte in the hope that understanding its function would uncover new methods of modulating immune responses like the one leading to transplant rejection. I will briefly and in layman’s terms attempt to describe some salient points immunologists have learned about T cell function,then describe some preliminary but very exciting studies that suggest new less toxic approaches for preventing transplant rejection may be on the horizon.

A normal, healthy adult human being has on the order of 100,000,000,000(10 to the 11th power) to 1,000,000,000,000 (10 to the 12th power) Tcells. Each of these T cells is constantly on the lookout as they circulate through various tissues and the blood stream for the one and only one target each is designed to recognize. The sensor that allows the T cell to recognize that target is called the T cell receptor, often abbreviated TCR, and the target recognized by an individual TCR is incredibly specific. T cells can routinely for instance recognize and take steps to kill a cancerous or infected cell and leave intact a neighboring cell that is not cancerous or is not infected. While each individual T cell can recognize only one target, we have such a large number of T cells that a large number (approximately 1,000,000,000or 10 to the 9th power) of targets can be recognized. The range of targets an individual’s T cells can recognize is known as the T cell repertoire.

Immunologists used to believe that if during its constant travels through the body a T cell happened to encounter its target, that the recognition alone would trigger the T cell to become activated.Further, that the activated T cell would make more copies of itself,secrete hormone-like factors called cytokines or interleukins, and”mature” in other ways such that the encountered target would be destroyed. Approximately 20 years ago however, scientists began making observations that called into question simple recognition induced T cell activation. A new theory called the “two-signal” model for T cell activation was proposed. That theory stated that for T cell activation to occur the T cell must not only encounter the one target it was designed to specifically recognize, but it must also simultaneously have another kind of T cell sensor triggered. That proposed second kind of sensor was called the costimulatory receptor and it was theorized to communicate to the T cell the “second signal” required to activate the Tcell. To further elaborate, this costimulatory receptor was theorized to not be specific for any one target but could be thought of as an on-off switch for the T cell. As per the two-signal model, each of the two classes of T cell’s sensors can be thought of as serving two very different but vitally important functions. The TCR has the difficult job accurately identifying a potential target, and the costimulatoryreceptor turns on the T cell once target recognition has occurred.

Most of the time the immune system does what it is designed to do with amazing accuracy; cancerous cells are destroyed, infections are successfully thwarted, and normal tissues are almost invariably left alone. Some illnesses however are caused when the immune system begins attacking a target that is counter-adaptive to health. Individuals with type 1 diabetes require insulin therapy for instance because for unknown reasons the body’s T cells have killed the insulin producing cells in the pancreas. Individuals who have received a life saving or health preserving organ or tissue transplant only to have that transplant later rejected by the immune system are also examples of how immune system responses can be counter-adaptive. All the medicines currently employed by clinicians to prevent these counter-adaptive immune responses act by impairing all T cells indiscriminately. Thus the steroids and the cyclosporine A that prevent the activation of an individual’s T cells recognizing a transplanted organ and thus block graft rejection, will also prevent the activation of that individual’s T cells recognizing,for example, a cytomegalovirus (CMV) infected cell.

Approximately 5 years ago, agents were developed that acted to interfere with the function of the T cells’ costimulatory receptor(s). The beauty of these reagents is that they allow the wonderful specificity of the immune response to be maintained. That is, it is believed that these agents will effect only those T cells encountering their target and making the critical decision (dependent upon costimulatory receptorfunction) whether to become activated. A corollary of the T signal model of T cell activation is that if a T cell encounters its target but does NOT receive the costimulatory signal required to activate it, that the event for the T cell is not neutral. Rather, that T cell eitherdies, or is “re-educated.” In other words, that T cell has learned thatit should not become activated even if it encounterS the same target atsome later date. Further, since a T cell can live for years, the immunere-education can also be long lasting.

Since 1992 a number of studies performed by investigators at the University of Chicago, the University of Massachusetts, the University of Michigan, the University of Pennsylvania, Emory University, Harvard University and within the U.S. Navy demonstrated that cost imulatory pathway blocking reagents would prevent the rejection of transplanted organs and tissues in rodents. The road to finding new ways to prevent transplant rejection however is littered with novel therapies that work wonderfully in rodents, but fail when tested in more complex species. Therefore, my colleagues in the Navy (LCDR Allan Kirk, Dr. Tom Davis)along with collaborators at the University of Wisconsin (Drs. StuartKnechtle and John Fechner) decided to test whether administering second signal blocking agents would work in a primate model to prevent the rejection of a transplanted organ. Our study was recently reported inthe Proceedings of the National Academy of Sciences (Volume 94, pages8789-8794, 1997). We found that rhesus monkeys given a mismatched kidney transplant and “second signal” blocking agents for the month after surgery, and none thereafter, not only tolerated the medicines without any apparent toxicity, but most strikingly displayed no evidenceof graft rejection for at least 6 months following the transplant. Wealso found that the immune system did not appear to be generally impaired by the therapy.

These studies need to be repeated and extended in additional animal studies, and the therapy needs to be studied in carefully designed human clinical trials. If our preliminary results hold however, then perhaps a new era in transplantation medicine may be on the horizon. For the time being, all patients currently under the care of a transplant physician and/or transplant surgeon are most strongly encouraged to take their medicines as prescribed with the hope that a better future is coming.

Editor’s note: If the ability to induce non-toxic and specific immunity is achieved, then it is doubtful that encapsulation would be required. The most significant problem will be where to get an inexhaustible supply of islets. Already work is well underway with xenotransplantation, the engineering of human stem cells and the expansion of human islets. One of the leading names to follow in the field of engineered cell lines is Dr. Christopher Newgard (seeĀ Engineered Cell Lines for Insulin Replacement in Diabetes: Current Status and Future Prospects); in islet cell expansion, keep your eyes open for work from Dr. Alberto Hayek of the Whittier Institute on the West Coast; for xenotransplantation Dr. Bernhard Hering from the University of Minnesota (The Future of Islet and Pancreatic Transplantation) and Dr. Camillo Ricordi of the Diabetes Research Institute in Miami.