Welcome to TXmnJim's
Transplant Information Articles

Coalition On Donation

牋牋

Here is some information to help you understand what an organ transplant recipient goes through.......

The Holy Grail of Organ Transplantation is "Donor Specific Tolerance." Despite tremendous improvements in the success rate of organ transplants, it is still necessary to suppress the immune system in order to prevent the graft from being rejected. The drugs used to do this cause many annoying side effects in the transplant recipient. And despite their use, organ graft rejection can still occur. For these reasons scientists are searching for a means to make the immune system tolerant to a specific organ donor. If tolerance is achieved, the toxic immunosuppressive drugs could be eliminated.
There are several types of rejection. "Acute" graft rejection occurs primarily in the first year after a transplant. Despite state of the art immunosuppressive drugs given in combinations, there is usually a 20-50 percent chance of acute graft rejection (depending on the organ transplanted). Fortunately, it is possible to control acute graft rejection with more intense immunosuppression in more than 90 percent of cases.Patients often wonder why more intense immunosuppression is not given in the first place to prevent rejection from beginning. This could be done. In fact, it is possible to give sufficient immunosuppression to entirely prevent all rejection. However, this is not done because it would cripple the immune system and the patient would die of infection. .Instead, enough immunosuppression is given such that rejection occurs slowly and is treated effectively in most cases. Modern immunosuppressive strategies utilize combinations of drugs so that no one drug has to be used in a high dosage. This avoids many of the side effects of the individual drugs which tend to occur more commonly with high dosages. Immunosuppressed patients are still more susceptible to infections, particularly viral infections. But most of the infections that occur in transplant patients are not life threatening.

Chronic rejection is completely different, and much less well understood. It occurs from months to years after the transplant and tends to occur slowly. It is more of a scarring process. While the latest immunosuppressive drugs have decreased the rate of graft loss due to acute rejection, the graft loss associated with chronic rejection has not changed very much. Furthermore, unlike acute rejection which can be treated effectively in most cases, chronic rejection is often untreatable and eventually results in graft failure in most patients that develop it. It is hoped that if true tolerance can be achieved, chronic rejection as well as acute rejection will be eliminated.

Donor specific tolerance implies that a treatment is given at the time of organ transplantation which results in indefinite graft function without the need for further immunosuppressive treatment. If true tolerance is achieved the recipient will accept further transplants from the same donor without the need for further treatment, but will reject transplants from any other donor normally. Essentially, this amounts to re-educating the immune system such that the new graft is considered to be a part of the body and no longer considered to be an "invader" or an "abnormal tissue" by the body. Tolerance can be generated in models of organ transplantation between rodents. In tests mice and rats are given treatments at the time of transplant and for several days or weeks, then discontinued. The animals become tolerant to the donor graft and accept other grafts from the same donor, while rejecting grafts from animals that were not the original donor. Many different examples of tolerance have thus been demonstrated.

Unfortunately, the same treatments that work in mice and rats have not worked in humans or other primates, at least until recently. In an article published Aug. 5,1997 in Proceedings of the National Acad. of Sciences, a group of doctors at the University of Wisconsin and the Naval Medical Research Institute have recently described two animals that were given a treatment for 28 days that appears to have produced tolerance. The animals in question are monkeys, and the grafts they received were kidneys from other monkeys. The treatment used was a combination of two drugs; one a drug called CTLA4Ig that prevents the immune cells that cause graft rejection called T-cells, from signaling each other. The other drug is an antibody that also binds to T-cells and prevents cells from multiplying. The end result is that the monkeys did not reject their grafts, which were still functioning normally 6 months after the transplant, despite the fact that they had been given no immunosuppression after the initial 28 day treatment.

So what does this discovery mean to transplant patients? First of all, it will be important that this observation is corroborated by other investigators. Secondly, it will be important to make sure that the grafts indeed function for years without rejection. And, additional tests will be necessary to know for sure if "donor specific tolerance" has been generated. If the treatment has simply rendered the monkeys "anergic" to foreign tissue, meaning that they do not respond to any foreign tissue whatsoever, then any infection could be fatal to the monkeys and therefore the treatment probably will not be clinically useful. Finally, it will be time to treat human patients with this therapy to see if it works. Generally discoveries like this take 5-10 years before they are available for routine therapy.

What about patients that have already received grafts and take immunosuppressants now? It is quite possible that the tolerance induction must occur at the time of a transplant, which would mean that these patients would be out of luck. On the other hand, it is also possible, although less likely, that this treatment could be used to make current recipients of organ grafts tolerate their transplanted organ without immunosuppression. The only way to know the absolute answer in this situation will be further animal experiments and trials in humans.

Even if the recent discovery turns out not to be the "Holy Grail" it is apparent that scientists are very much on the trail to donor specific tolerance in humans. Several groups are studying the effects of including immune cells with a transplanted organ in the form of a bone marrow graft from the donor. The idea is that the donor's immune cells may somehow cause the body to accept the donor organ. This idea grew from the observation by Dr. Thomas Starzl at the University of Pittsburgh that some liver transplant patients that have had stable graft function for many years can be safely withdrawn from all immunosuppression. At this point it looks like most patients will have rejection if this is done, but in some patients the graft continues to work fine. When Dr. Starzl studied the patients that seemed to be tolerant he found that donor cells were throughout the recipient's body.

He termed this finding "microchimerism". This led to the supposition that facilitating microchimerism may lead to tolerance. Studies are in progress to determine if this strategy will work. Overall the future looks bright for the prospect of donor specific tolerance in humans. However, it is purely speculative to guess when this will be achieved. One thing is likely though: whomever makes tolerance work in humans will almost certainly get the Nobel Prize in Medicine.

Higher success rates in organ transplantation are due to advances in surgery, tissue preservation and drugs that prevent rejection. Allocation of organs and selection of recipients involve certain ethical dilemmas. T-cells and B- cells are two types of disease-fighting cells of the immune system. Healthy organs should match the genetic makeup of the recipients. Organ transplant recipients must take multiple medications for the rest of their lives to prevent rejection. Cyclosporine and tacrolimus inhibit T-cells but have little effect on B-cells which produce antibodies against infections. Corticosteroids, zathioprine, cyclophosphamide and mycophenolate mofetil (CellCept) are additional medications used to prevent rejection. Immunosuppressive therapy costs $5,000 or more yearly. Adverse effects of immunosuppressive therapy include hypertension, increased cholesterol and weight. Kidney and liver damage can occur in immunosuppressive therapy. A donor card or a driver's license may be used to indicate that a person is willing to be an organ dono, although this in no way guarantees that his/her wishes will be carried out. Tell your family, tell your spouse, put it in your living will. Don't take your organs to heaven. Heaven knows we need them here!

Antirejection Antibody Could End
Lifelong Use of Immunosuppressants.

TUCSON, AZ. -- September 18, 1997 -- Ongoing preclinical studies of an anti-rejection antibody have established its ability to prevent and reverse organ rejection while leaving the immune system intact. The CD45RB antibody induces antigen-specific tolerance that may allow transplant patients to stop the chronic use of toxic immunosuppressive drugs. The antibody also shows promise for use with autoimmune diseases.

Rejection continues to be the major impediment to successful organ transplantation. Current transplant technology requires chronic use of steroids and global immuno suppressants, such as cyclosporine, to prevent rejection. These drugs leave patients vulnerable to infection, cancer and other diseases. Antibodies to reverse or delay rejection, such as Orthoclone OKT3(tm), eliminate most of the body's lymphocytes and so are given only acutely.

Besides the serious side effects, present immunosuppressant therapy is only partially successful. About 60 percent of kidney transplant patients have at least one rejection episode in the first three months after surgery. None of the current immunosuppressive agents offer the hope of immune tolerance without chronic immunosuppressant use.

The antigen-specific tolerance created by the CD45RB antibody presents a safe, new approach to prevent and treat transplant rejection and autoimmune diseases in humans. Although the mechanism is not completely understood, the antibody interrupts the immune activation process without depleting the entire T cell population. It reacts to a specific epitope on the CD45RB isotope, a subpopulation of cells that activate in response to particular antigens.

This antibody was developed by Andrew I. Lazarovits at the Univ. of Western Ontario and Sibrand Poppema of the University of Groningen in the Netherlands. Through its Venture Development Group, Research Corporation Technologies has collaborated with Lazarovits and Poppema to follow up on their earlier work and conduct the preclinical studies needed to advance the technology.

RCT's preclinical development plan builds on results the researchers published in the April 1996 issue of Nature. In those studies, mice given a short course of therapy with the CD45RB antibody at surgery survived kidney transplants and had normal renal function without additional treatment. A second group of mice that received transplants with no immunosuppressive therapy developed acute rejection that the CD45RB antibody then reversed.

Results from the preclinical studies show a short course of the CD45RB antibody induces tolerance in mice to hearts and pancreatic islets transplanted from the same (allografts) and different (xenografts) species. The antibody also prevents diabetes in mice predisposed to the disease and prevents autoimmune encephalitis, a model of multiple sclerosis. Preliminary results from studies of other disease models, such as arthritis, are encouraging. Initial data from ongoing kidney transplant studies using a mouse anti-human CD45RB antibody in monkeys also look favorable. The results are similar to Lazarovits and Poppema's rodent kidney studies published in Nature showing transplant rejection reversal and indefinite animal survival.