The advancements in present day technology have still fallen short of combating the two major barriers that limit wider adoption of organ transplantation; namely immune rejection and side effects that result from immune suppression. Several strategies have been proposed to artificially manipulating dendritic cells (DC), found responsible for eliciting primary immune response and tolerance, to generate â€œtolerogenicâ€ DC, which holds greater therapeutic potential for autoimmune diseases and allograft rejection. Now, a recent study has zeroed-in on a potential strategy to overcome the complications through the development of degradable microparticles that are capable of delivering major histocompatibility complex, class I, G (HLA-G), a natural immune suppressor, directly into DC.
Anatolij Horuzsko, Reproductive Immunologist, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Medical College of Georgia (MCG), and colleagues, investigated the efficacy of the novel technique in mice models with skin grafts. The study results showed that the double-coated microparticles possessing the dendritic cell marker and the preferential ligand, HLA-G, is more efficient in targeting and modulating DC, when compared to those without the marker.
The delivery of HLA-G via the novel technique inhibits certain receptors present on the DC including immunoglobulin-like transcripts 2 (ILT2), ILT3, and ILT4. This in turn activates a signaling pathway that produces several suppressive molecules that confer protection to transplanted organs or tissues. Apart for transplantation, the microparticles hold promise in treating autoimmune disorders such as inflammatory bowel disease, arthritis, and multiple sclerosis.
A similar targeting concept could be adopted for inhibiting the aberrant expression of HLA-G in cancers. Apart from the direct inhibitory effect of HLA-G on immune responses, numerous studies have reported its role in inducing the production of suppressor/regulatory cells and in long-term immunomodulation. The immune suppressor has been identified as the key effector molecule of immumological changes during pregnancy in preventing maternal immune responses to genetically variant fetal tissues.
Immunosupressive agents are widely adopted for reducing the incidence and severity of rejection after transplantation procedures. However their long-term use is associated with certain adverse effects including nephrotoxicity, arterial hypertension, dyslipidemia, and post-transplant diabetes mellitus. Also, the use of such drugs suppresses the entire immune function, making the patients more vulnerable to cancer and other infections. With the requirement of only a few weeks of treatment, the novel HLA-G microparticle promises torevolutionize the currently used immunosuppressive therapies. However, the efficacy of the new strategy for organ/tissue transplantations needs to be corroborated through larger trials.
1. Microscopic “beads” could help create “designer” immune cells that ignore transplanted organs. Press Release. Medical College of Georgia. Last accessed July 18, 2009.
2. Wu J, Horuzsko A. Expression and function of immunoglobulin-like transcripts on tolerogenic dendritic cells. Hum Immunol. 2009 May;70(5):353-6.