Future of Transplantation-3
Immune Tolerance - an important goal in lung transplantation, as in other types of solid organ transplant, is for withdrawal of corticosteroids from standard immunosuppressive regimens. Successful withdrawal of corticosteroids was reported in a small group of lung transplant recipients. Patients were considered for corticosteroid withdrawal if they had stable pulmonary function( <10% change in FEV1 over the preceding 6 months) and no episodes of acute rejection or evidence of chronic rejection within 6 months proior. The search for tolerance therapies that would thwart the alloimmune response following organ transplantation while preserving the patient's protective immune response has been a formidable goal for clinical immunologists. Only a few promising new therapies have reached the early stages of human clinical development. In contrast, the use of T-cell depleting induction therapy has become widespread, and new trials have been designed with immunosuppressive drug withdrawal in mind. In the course of these investigations, however, what has become increasingly clear is that the distinctions between immunosuppression and tolerance
have been blurred as the success and durability of the therapies rely as much on the state of the organ and organism as they do the mechanism of action of the drug. ( Source: American Journal of Transplantation, July 2003)
Study Finds New Cells That May Trigger Chronic Rejection of Organs - Researchers at the University of Pennsylvania report that otherwise innocuous cells within donated tissue may be responsible for triggering the chronic rejection of transplanted organs. Chronic rejection -- believed triggered by certain highly immogenic white blood cells from the donor, carried within the transplanted organ - can occur years later. Studies showed that donor endothelial cells, which are the cells that line blood vessels, activate the transplant recipient's CD8+ "killer" T cells directly triggering the rejection response. (Source: Transplant Week - March 2002)
Stem cells shown to regenerate damaged lung tissue for first time - Researchers have demonstrated that adult human stem cell transplantation results in spontaneous cell regeneration in damaged lung tissue. The study further supports an existing body of research that suggests blood-
and-marrow- derived stem cells have the capacity to become many different human tissues. This finding is of note not only for its novelty as aregenerative mechanism of the lung, but also for its vast therapeutic implications for any number of lung disease. (Source: Health & Medicine Week, September 15, 2003)
An Alternative to lung transplantation - Lung Volume Reduction Surgery(LVRS) has been used increasingly in adults for treatment of breathlessness caused by severe emphysema. It is of particular benefit to patients with a heterogenous anatomic distribution of emphysema, with obvious target areas for resection, as it allows an improved chance of reclaiming function from surrounding compressed lung. We report on an 8 year old male with obliterative bronchiolitis in whom LRVS has been used as a measure to significantly improve quality of life and avoid the immediate need for lung transplantation. (Source: Pediatric Pulmonology, Volume 36, Issue 4 - August 22, 2003)
myfortic. - The new immunosuppressant from Novartis receives first major approval - in Switzerland Novartis announced today that the Swiss Agency for Therapeutic Products, Swissmedic, has granted marketing authorization for its medicine myfortic. (mycophenolate sodium), thus making Switzerland the first major country in the world to approve the product. myfortic. is used in transplantation medicine for the prevention of organ rejection. myfortic. is a specially designed formulation of the sodium salt of mycophenolic acid (MPA), a key immunosuppressant used in Neoral.-based combination therapies in transplantation. Unfortunately, dose modifications and discontinuations (e.g. due to GI side effects) are seen with the only currently available MPA formulation, mycophenolate mofetil, (MMF) for transplantation on the market. Frequent changes in MPA dosage are associated with poorer outcomes, such as higher incidence of graft loss, in the transplant recipient. myfortic. is an advanced, enteric-coated tablet containing MPA sodium developed to help protect the upper GI tract from known side-effects of MPA. Improvement in GI tolerability may lead to fewer dose reductions or discontinuations. Two major pivotal clinical studies involving 748 patients worldwide have demonstrated that enteric-coated myfortic. is a highly potent and well
tolerated immunosuppressant for new renal transplant patients and also that transplant patients already taking other MPA drugs can be safely switched to myfortic..
Mixed chimerism - This strategy is based on the transfer of donor bone marrow cells to the recipient under cover of host T-lymphocyte depletion prior to transplantation. The aim is to remove immunoreactive antibodies to the donor graft, inducing central tolerance to the transplant. The more severe irradiation methods which have been used in the past to deplete T-lymphocytes are now rapidly being displaced by milder techniques, bringing this approach closer to clinical reality. To date, mixed macro-chimerism techniques have shown good results with skin in rodents; kidney to heart transplants in pigs; kidney transplantation in primates. To date, mixed macro-chimerism techniques have shown good results with skin in rodents; kidney to heart transplants in pigs; kidney transplantation in primates.
T-cell depletion by anti-CD3 immunotoxin - The goal of this approach is to develop peripheral tolerance using an immunotoxin to deplete T-lymphocytes locally in the graft. A CD3 monoclonal antibody linked to genetically engineered diphtheria toxin to create an immunotoxin has shown very promising results in primate renal allografts. After depleting T-lymphocytes with this immunotoxin molecule, the remaining T-cells canbe 're-educated' in the presence of the graft, thereby inducing
tolerance. This research is being developed by Novartis in conjunction with the National Institutes of Health in the USA.
Blockade of co-stimulatory signal - This strategy uses a pharmacological approach to blocking co-stimulatory molecules in the T-lymphocyte pathway, using antibodies against CD28-B7 or CD40-CD40L. It is the mildest approach to tolerance induction currently being studied, and has shown good results in non-human primates. Long-term intermittent immunosuppression may be necessary to supplement this technique. Gene therapy in transplantation Gene therapy holds a potential key to improved treatment of many diseases, and there has already been significant progress in conditions such as cystic fibrosis. Novartis is now investigating the use of gene therapy to pre-treat donor grafts before rejection, and this innovative approach is in active pre-clinical development. Conceptually, this process involves treating an organ prior to transplant to activate or dampen specific genes. The goal of this process is to modify the genes known to be involved in the very early process of rejection, helping to prevent the immune system from recognizing the organ itself and thus avoiding the initial damage to the graft which occurs at the time of transplantation. One advantage of treating the organ before transplantation is that this allows the viral vector to be targeted to its site of action, thus avoiding many of the systemic problems (such as an immune response to the viral vector) which are encountered when gene therapy is administered intravenously.
