Organ Transplants without Immunosuppressant
IL-2 Complexed with Antibody Stimulates Tolerance
Apr 14, 2009
Organ transplants under the best of circumstances require careful matching of donor and recipient to minimize histocompatibility problems, followed by aggressive suppression of rejection. The recipient is in constant danger of inadequately suppressing rejection and losing the organ, or oversuppressing immunity and succumbing to infections or cancer. A new study explores an alternative approach that teaches the recipient body to accept donor tissue as self.
Tolerance -- Deletion of Self Recognition
The immune system is vigilant to invading pathogens, because it can recognize foreign molecules. Two different sets of recognition molecules, T cell receptors and antibodies are displayed on the two major types of lymphocytes, T cells and B cells, respectively. Each T cell and B cell produces a different recognition molecules as the result of unique DNA rearrangements during their development in the thymus and bone marrow, resp. During development immune cells producing either T cell receptors or antibodies that bind to self molecules, are eliminated. More than 90% of the possible recognition diversity is eliminated to avoid dangerous attacks on self cell, i.e. autoimmunity.
Tolerance -- Suppression of Immune Response to Self
In addition to the deletion of self-recognition by T and B cells, another system actively suppresses immunological attacks on specific targets. This system is controlled by T regulatory cells, Tregs, that produce local signals, cytokines, to silence T or B cells that react defensively to self or safe molecules. It is the Tregs that are dysfunctional in allergies and autoimmunity.
Interleukin-2 Stimulates Tregs
One of the signals, that stimulates a T cell to differentiate into a Treg is interleukine-2, IL-2. IL-2 under different circumstances can trigger the development either into an active T cell that is needed for defense against pathogens, or into a Treg that can neutralize unnecessary response to food.
IL-2 Complexed with Antibody Protects against Organ Rejection and Autoimmunity
During the last decade, a series of research projects have attempted to utilize interleukins to direct the immune system to bolster immunization and minimize inappropriate or undesirable immune responses. Recent development of complexes between interleukins and antibodies against interleukins have been particularly powerful. IL-2/antibody complexes have been used to stimulate Treg amplification prior to organ transplants in experimental animals and have eliminated the need for subsequent immunosuppression. The IL-2/antibody treated animals appear to become permanently tolerant to the donor tissue. Similar treatment has also been effective in providing protection against autoimmune disease development.
IL-2/antibody treatments are now being investigated to treat a variety of degenerative, autoimmune and cancer diseases. This immunological breakthrough may be the therapeutic silver bullet of the 21st century.
Reference:
Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, Grey ST, Sprent J. 2009. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med. Mar 30. [Epub ahead of print]
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