Miami, FL (August 27, 2002) — Studies conducted at the Diabetes Research Institute have shown that a bone-seeking radioactive compound can successfully re-educate the immune system of mice, enabling them to accept transplanted bone marrow for extended periods of time without observed negative side effects.
One injection of the short-acting compound Samarium-Lexidronam (153 Sm-L) given prior to bone marrow, and an antibody to impair T-cell activation, was shown to be a highly effective strategy resulting in long-lasting chimerism.
Chimerism is an immunological state in which newly transplanted tissues seem to be more easily “tolerated” by the host. This new use of Samarium, a drug used in cancer therapy, may have a wide range of clinical applications beyond helping recipients tolerate transplanted organs and tissues, including the treatment of hematological disorders and related malignancies, autoimmune diseases like diabetes, and infectious diseases.
The results of these novel series of experiments are being announced at the XIX International Congress of the Transplantation Society in Miami.
“In our experiments we address one of the major hurdles still to be overcome if islet cell transplantation is to continue evolving as a promising therapy for type 1 diabetes: the need for life-long immunosuppression that patients have to take for their transplanted cells to survive,” explains Luca Inverardi, M.D., research professor of medicine, microbiology and immunology, and senior investigator of the study.
“As islet transplantation becomes more successful and more patients are freed from insulin requirements, science must direct its efforts to finding less harmful alternatives to the anti-rejection drugs that are currently available.”
For several years, scientists have pursued different avenues for establishing chimerism, a much sought-after equilibrium between immune cells of the donor and cells of the recipient that is thought to be a pre-requisite for the long-term, drug-free acceptance of transplanted tissues and organs. This type of “re-education” of the immune system has typically relied on harsh pre-conditioning of transplant recipients, usually through total body irradiation or cytotoxic drugs to destroy the existing immune system before reconstituting it with donor cells.
These extreme approaches are acceptable risks for diseases that are immediately life-threatening, such as cancer, but not for others such as diabetes. In order to develop a clinically relevant strategy for tolerance induction in diabetes, the DRI team searched for a combination strategy that would not only be effective, but also clinically practical. In this study, treatment based on 153Sm-L and short administration of an antibody known to impair the activation of T-cells resulted in enhanced and stable chimerism levels after bone marrow transplantation, when compared to untreated control animals.
When these chimeric animals had their immune systems challenged with skin grafts taken from the same mouse strain as the bone marrow donor, a large proportion of the animals accepted the skin grafts. Importantly, skin grafts from a third-party strain were rejected, suggesting that donor-specific tolerance had been truly been achieved using this strategy. Control animals that did not receive bone marrow and conditioning treatment invariably rejected skin grafts within 15 days from transplantation.
“This is a new application of an agent that functions like a bone-seeking smart bomb, which is only active in the body for a very short period before being eliminated,” adds Dr. Inverardi. “It is already in clinical use for the management of pain in bone cancer, and it may prove to be the basis of a new transplant strategy that enables us to reduce or eliminate altogether our need for anti-rejection agents in the future.”
Mitra Zehtab, MD, MBA