Future of Transplant - 1
To the Moon!! Well not quite...but there are many new therapies being tested for possible new medications in the world of transplant and of course for lung, heart recipients. Here is a collection of what is in the works, and hopefully will be a success and we will benefit from them.
<st1:City><st1:place>New approach to battling organ rejection (ADDED 9/19/04) WASHINGTON (AP) -- Scientists have created a way for transplant recipients to inhale an anti-rejection drug deep into their new lungs -- suggests the therapy may increase patients' chances of survival four-fold. This inhaled version of cyclosporine remains experimental. Its creators at the University of Pittsburgh are working with a drug company to seek government approval for its sale. "It makes good sense to apply the immuno-suppressive agent right to the location where the problem exists," said Dr. Ed Garrity, director of lung transplants at Loyola University Medical Center. So Pitt researchers dissolved powdered cyclosporine, donated by Novartis Pharmaceutials, into another chemical so it can be inhaled as a mist using a nebulizer, much like certain asthma medications are.Then, in a study funded by the National Institutes of Health, they divided 56 new lung recipients into two groups. Everyone got standard anti-rejection treatment. But half also were given the inhalable cyclosporine and half a dummy nebulizer, to use three days a week for two years after their transplant.Patients were tracked for two to five years. Eleven percent who inhaled cyclosporine died in that time period -- compared with 47 percent who got the placebo. A mixture of lung biopsies and lung-function tests showed the cyclosporine prevented chronic rejection, he added. Pitt researchers since the 1990s have used inhaled cyclosporine in about 150 patients already suffering severe rejection, saying it can buy them some time. But other lung specialists have been skeptical because, unlike the new prevention research, that treatment hasn't been offered in a strictly controlled study.
FTY720 immunomodulation: optimism for improved transplant regimens (ADDED 9/19/04) --FTY720 has been shown to be highly effective for preventing graft rejection in preclinical models of cardiac, renal, and hepatic transplantation. FTY720 can be used safely in combination with CsA and everolimus. Overall, these synergistic effects suggest that FTY720 has the potential to provide a real improvement in the efficacy and tolerability of future immunosuppressive regimens.(Source: Transplantation Proceedings March 2004)
Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome (ADDED 9/19/04) --Background. The subset of CD4+CD25+ regulatory T cells, recently identified in humans, may play a central role in the regulation of immune tolerance to graft survival.Methods. This study assesses the frequency and functional profile of CD4+CD25+CD69- cells in the peripheral blood of lung transplant recipients (>3 years from transplantation), 10 of whom were in a stable clinical condition and 11 of whom demonstrated chronic rejection (bronchiolitis obliterans syndrome). We also studied a group of seven healthy subjects.Results. The frequency of CD4+ T cells expressing CD25 (CD4+CD25+) and the highest levels (CD25high) were lower in patients with bronchiolitis obliterans syndrome compared with healthy subjects and subjects in a stable clinical condition (P =0.01). Purified CD4+CD25+ cells exhibited a regulatory functional profile in vitro: they were hyporesponsive, suppressed the proliferation of CD4+CD25- cells, and produced interleukin-10.Conclusion. These results provide in vivo evidence that peripheral CD4+CD25+ T cells may represent an important regulatory subset in lung transplantation. (Source: Transplantation: 15 March 2004)
The evolving experience using everolimus in clinical transplantation (ADDED 9/19/04) Everolimus is a derivative of sirolimus, a macrocyclic lactone. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. The CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation. (Source: Transplantation Proceedings; March 2004)
USE OF 18FDG-PET TO DISCRIMINATE BETWEEN INFECTION AND REJECTION IN LUNG TRANSPLANT RECIPIENTS (ADDED 9/19/04)
18F-fluorodeoxyglucose (18FDG) uptake measured by positron emission tomography (PET) allows assessment of neutrophil activity in vivo and is increased in patients with airway inflammation or infection. Because infection but not rejection elicits a highly neutrophilic response, we assessed the ability of this non-invasive technique to differentiate these two events in lung transplant recipients. 18FDG-PET was measured in 15 patients classified by clinical, radiologic, and pathologic criteria. 18FDG-PET signal was increased with proven infection but not when no infection was identified (mean [standard error of mean]: 8.00 [1.81] and 3.16 [0.61], respectively [P = 0.021]. Rejection alone did not increase the signal. These data confirm that neutrophil activation is not a feature of acute rejection and indicate that a high 18FDG-PET signal is indicative of infection but not rejection in lung transplant recipients. This non-invasive and repeatable test could reduce the number of transbronchial biopsies required during episodes of breathlessness after lung transplantation.(Source: Transplantation. May 15, 2004)</st1:place></st1:City>
Carbon Monoxide: Poison Gas or Anti-inflammatory Drug? (ADDED 9/1/05) Carbon monoxide, a poisonous gas that kills thousands of Americans every year, could turn out to be a life-saver for patients recovering from organ transplants, strokes or heart attacks, according to new research from the University of Michigan Cardiovascular Center. In a recent study, U-M scientists found that inhaling small amounts of carbon monoxide for several weeks after transplant surgery prevented the development of a lethal inflammatory reaction in experimental mice receiving transplanted trachea, or windpipes.If carbon monoxide therapy works as well in human patients as it does inmice, it could prevent an inflammatory response, called obliterative bronchiolitis, which develops in nearly 50 percent of all patients who receive a lung transplant from an unrelated donor. OB is the most common complication following a lung transplant in humans and the most deadly. It occurs when the patient’s immune system rejects the transplanted lung and sends an army of T cells to attack and destroy the foreign tissue. “No one is sure exactly how it happens, but the small airways in the lung swell and become progressively smaller until the patient cannot breathe,” says David J. Pinsky, M.D., the J. Griswold Ruth, M.D. & Margery Hopkins Ruth Professor of Internal Medicine and chief of cardiovascular medicine in the U-M Medical School, who directed the research. Pinsky’s research team focuses on the relationship between carbon monoxide and nitric oxide – two poisonous gases produced by different types of cells in the body. U-M research findings suggest that a patient’s chances of living or dying after a lung transplant depend, in large part, on the outcome of an internal power struggle between two enzymes that control cellular production of these gases.“Hmox, or heme oxygenase enzyme, is responsible for the synthesis ofcarbon monoxide,” Pinsky explains. “It was first identified as a heatshock protein induced under stress conditions to help protect cells from damage. Hmox expression increases in human lung transplant patients with OB.“Nitric oxide synthase, or iNOS, is the enzyme responsible for the synthesis of nitric oxide,” Pinsky adds. “When it’s expressed in endothelial cells in blood vessels, it causes them to dilate an relax. But when it’s expressed in epithelial cells in airways, it generates a flood of leukocytes that trigger an inflammatory response.Expression of iNOS also increases during lung transplant rejection.“We think that Hmox and carbon monoxide are the body’s way of trying to limit tissue inflammation and injury induced by iNOS and nitric oxide during transplant rejection,” Pinsky says.
Long-term observation after simultaneous lung and intra–bone marrow–bone marrow transplantation -(ADDED 9/1/05) It has been reported that bone marrow transplantation (BMT) induces specific tolerance to donor organs. We have recently discovered a new method for BMT, which is called intra–bone marrow (IBM) BMT, in which bone marrow cells (BMCs) are injected directly into the bone marrow cavity. However, the recipients treated with lung allografts plus IBM-BMT, which showed either mixed chimerism or full chimerism of hematopoietic cells, did not show symptoms of graft rejection or graft vs host disease, even without the use of immunosuppressants. ConclusionsThese results suggest that simultaneous lung transplantation and IBM-BMT(but not conventional BMT) is effective in inducing persistent tolerance without the use of immunosuppressants. (SOURCE: The Journal of Heart and Lung Transplantation)
