Selective elimination of autoimmune B cells using novel CAR-T technology based on antigen decoy

Few days ago journal Science published very interesting study describing a novel approach of treating autoimmune [auto-antibody]-dependent diseases. Called chimeric auto-antibody receptor (CAAR) T cell technology, this method can selectively eliminate autoantigen specific B cells in autoimmune diseases such as Pemphigus vulgaris, lupus, Myasthenia Gravis, Graves diseases and so on.

This new technology is based on a simple idea: antigen decoy. For example, during pemphigus vulgaris autoimmune B cells secrete autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg3) that causes severe skin inflammation. Short-term management of diseases is achieved by total B cell depletion, but disease returns. The authors reasoned that if engineered T cells would express Dsg3 as a CARs, such antigen decoy CAAR T cells would selectively engage disease-causing anti-Dsg3-specific auto-antibody producing B cells. Such interaction should eliminate only Dsg3 specific B cells, sparing normal, infectious-specific B cells.

Indeed, the authors showed that CAAR-T cells expressing Dsg3 as a CAR construct (EC1-4 CAAR) can selectively interact with Dsg3-specific autoimmune B cells in vitro.  

More importantly in vivo NSG mice experiments confirmed that Dsg3 CAAR T cells could selectively eliminate human Nalm6 CD19+ B cell line expressing autoimmune Dsg3-specific receptors (PVB28/F779). In addition the authors claim that Dsg3 CAAR-T cells did not interfere with normal human skin epithelial functioning expressing Dsg3's natural ligand desmocollins.

In summary, if the results of this study is confirmed by other groups it would open up a new path for treating auto-antibody dependent autoimmune diseases.

David Usharauli

Chromogranin A is a disease-driving auto-antigen in type I diabetes

Type I diabetes is autoimmune disease leading to destruction of insulin-secreting endocrine β islets in pancreas and glucose intolerance. NOD mouse strain represents well established model of human type I diabetes. So far, researchers identified several potential auto-antigens targeted by self-reactive T cells, out of which so far only mutation in insulin B chain (B:9–23) showed effect on disease progression.

Now, this Cutting Edge study in Journal Immunology showed that absence of another auto-antigen, Chromogranin A (ChgA), fully protected NOD mice from diabetes development.

First, the authors showed that β islets of NOD.ChgA^-/- could not activate ChgA-specific T cell clones in an in vitro assay (reactivity to other auto-antigens insulin and IAPP was intact).

Importantly, the authors showed that NOD.ChgA^-/- mice were completely protected from development of diabetes [measured as excess of glucose in urine samples].

Finally, the authors showed that NOD.ChgA^-/- mice showed minimal β islets inflammation (insulitis) but developed comparable salivary gland inflammation (sialitis), implying that Chromogranin A effect was strictly β islets selective.

In summary, this study showed that at least Chromogranin A is necessary and sufficient for development of diabetes in NOD mice. Still, it is puzzling that NOD.ChgA^-/- mice is protected from diabetes when they still expressed another dominant auto-antigen insulin [because earlier study showed that NOD ins1^-/- ins2^-/- mice were protected from diabetes development too]. If both auto-antigens are "priming epitopes" then both NOD.ChgA^-/- and NOD ins1^-/- ins2^-/- mice should have developed diabetes. Strange.

David Usharauli