Bystander control of immunity to autoantigens and therapeutic proteins.

Autoimmunity is an important cause of ill health in need of better, less toxic therapy. Recently, there has been a substantial change in our perception of how autoimmunity arises. It appears that in many, perhaps most, diseases that the onset of autoimmunity is related to failure of usually very effective regulatory mechanisms. Specific subpopulations of T cells (T regulatory cells or Tregs) are newly recognised as among the most important regulators of immune and autoimmune responses. Tregs are T cells that recognise self, but instead of responding in a damaging way, as happens in autoimmune disease, respond in a way that not only causes no direct self-harm, but also prevents harm being caused by other T cells in the vicinity.
I propose to investigate initially kidney specific T regulatory cells as preliminary work indicated they can be found in the blood of healthy people and could be useful in therapy of renal autoimmunity (important in ~20% of dialysis-requiring renal disease) but I am particularly excited to test a novel approach we have devised that could make Treg therapy much more widely applicable, for example in preventing patients treated with ‘biological‘ therapies developing inhibitory immune responses.

There is now good evidence that regulatory T cells (Treg) can be used to deviate immune responses, particularly well-characterised immune responses in which relevant antigens and epitopes are known.
In the kidney, the Goodpasture antigen ( 3(IV)collagen NC1) is a uniquely well characterised glomerular autoantigen for which fine peptide specificity of the immune response is known in health and in disease. Two different approaches show that the dominant response is regulatory in health and after spontaneous recovery from disease (Kid. Int 2003, 64:1685, J Am Soc Nephrol 2003, 14:2801).
I will first test the hypothesis that most 3(IV)NC1-reactive cells in healthy individuals are Tregs, and compare their properties and numbers in patients with recovered disease and in some patients with active disease. This will evaluate the role of any balance in 3(IV)NC1 Tregs and effecter T cells (Teff) in health and autoimmune disease, and provide a platform for the second aim, which is to propagate Tregs to the Goodpasture antigen and characterise their regulatory capacity. Regulation by 3(IV)NC1 Tregs will be assessed from their influence on the proliferation of Teff cells specific to tetanus toxoid (most individuals are immune to tetanus toxoid) responding to conjugates of 3(IV)NC1 and tetanus toxoid.
The glomerular basement membrane and 3(IV) are damaged in all inflammatory (and in some non-inflammatory) glomerular diseases, and it seems certain that 3(IV)NC1 will be processed by the same antigen presenting cells as those are driving the disease. This raises the possibility that Treg recognising 3(IV)NC1 could suppress (‘bystander suppression‘) T cells important in pathological glomerular immune responses, and therefore have a much broader potential therapeutic application. In the third part of the work the potential for bystander suppression will be tested. Initially we will test the ability 3(IV)NC1-specific Treg to suppress Teff responses to 5(IV)NC1, the closely related target of autoimmunity in some of our patients with Alport‘s disease (inherited absence of 5(IV)NC1) who have received 3(IV)NC1-containing kidney transplants.
The proposed experiments will certainly enrich substantially our understanding of the role of Tregs in spontaneous autoimmune renal disease in man. If bystander suppression is shown to be sufficiently potent to influence clinically important immune responses, then the work will open up very promising new therapeutic approaches to controlling renal autoimmunity even where the renal autoantigens are not known, and could be extendable to controlling other undesirable immune responses such as those to therapeutic proteins (e.g. factor VIII).