Immune system involvement in TB

Tuberculosis is one of the diseases eliminated from occidental countries, even if few cases are reported every year. Granuloma formation into lung is the fundamental characteristics of this disease and the involvement of our immune system in this process is argued since long time. In advance of publication number of Cellular and Molecular Immunology an important paper illustrates how our immune system has a consistent role in granuloma formation and which kind of T cell are involved.

The comparison between blood samples derived from Tuberculosis patients or healthy donors demonstrated that the presence of a special group of T cells – namely the IL 17 producing γδ T cells- in peripheral blood was significantly higher in patients than in healthy donors. In vitro re-stimulation with tuberculosis mycobacterium antigen generated an increase in IFNγ producing T cells ratio in patients than in healthy donors, while the ration of IL17 producing cells was similar within two groups. These data were consistent with other results obtained in mouse model and confirmed the role of IL17 in granuloma formation. The identification of γδ T cells as major IL17 producer may arise some advantages for possible pharmaceutical treatment, but further elucidations are required to better understand all the mechanism at the basis of this complex disease.

Novel small molecule inhibitor has immunosuppression properties

Immunosuppression is one approach to care some autoimmune diseases, such as rheumatoid arthritis. Etarnercept and cortisone are currently used to care these disorders. In Nature Medicine has been recently published a work that describes a novel possible therapy for this kind of disease. Scientists focussed their attention on small molecule inhibitors of immunoproteasome. This cellular compartment has been identified in monocytes and lymphocytes and is specialized in generating MCH I peptides.

The selective inhibitor of LMP7, a specific protein belonged to immunoproteasome, down-regulated the expression of MCH I complex and reduced the level of some cytokines, for instance IL23, IL6 and TNF. All these molecules are implicated in the autoimmune response in rheumatoid arthritis. The expression of other cytokines were tuned in following inhibitor exposure. The small molecule inhibitor could have pleiotropic effects of various cell types, by ameliorating drug efficacy. In animal models, indeed, this molecules gained better results than Etanercept in TNF blockade and consequently showed faster resolution of symptoms of immune disorders. This study represents a great hope for all people that are affected by rheumatoid arthritis, but a lot of work still to be done before entering in clinical phase.

Small molecule inhibitors and resistance

A great challenge in academic labs and pharmaceutical industries is the identification of small molecule inhibitors that could specifically target proteins involved in human diseases.
To do this, the most important step is the knowledge of biochemical features of the target protein. Human diseases associated to the target are usually well understood and the target has been previously validated: this means that its inhibition determines a recovery of normal cellular functionality.

X-ray crystallographic analysis and SAR (structure activity relationship) studies are crucial to identify and improve small molecules; otherwise, high throughput screening are performed, this route is usually followed by pharmaceutical or biotech companies that dispose of instrumentation to run the screening and manage data. Several small molecules identified as potential drug in one disease are tested in clinical studies in order to bypass resistance problems that could arise during long term treatment. Indeed, during this therapies a natural selection of mutations that provide the restoring of protein target activity, happens and makes useless the treatment.
Nevertheless, it’s necessary to continue research of small molecule inhibitor, especially in view of good results obtained, for instance, in tumoral diseases.