Therapeutic Modelling and cis-Regulatory Genetics

Avrion Mitchison

Avrion Mitchison

A major aim of immunotherapy is to manipulate the immune response so as to deviate it from a predominant Th1 pattern (pro-inflammatory) to one of Th2 predominance. This is likely to be of value in autoimmune disease and in transplantation, while deviation in the reverse direction would be of value in atopy. Deviations of this sort have not yet been adequately incorporated into a mathematical model, but we believe that this could be achieved fairly easily within IMMSIM. On the basis of current experimental data we believe that the following relevant variables could and should be incorporated. Our hope is that modelling would enable us to evaluate the relative importance of these variables (making allowance for what can most easily be manipulated), and might indicate which ones could most usefully be combined.

Variable Favours Th1 differentiation Favours Th2 differentiation
Affinity of MHCII for epitope High Low
Affinity of TCR for epitope High Low
Concentration of epitope High Low
Local ratio of Th1/Th2 cells High Low
(Level of IL-12R expression) High Low
Level of MHC expression High Low

The last two variables are considered relevant on the basis of genetic rather than strictly experimental data, and the level of IL-12R expression (the Tpm1 gene effect) is placed in brackets because it would seem harder to incorporate in IMMSIM. The effect of all of these variables can be jointly summarised as signal attenuation favours Th2 differentiation, a rule that is backed up by a growing body of data obtained from treatment with signal-blocking agents.

The use of genetic data in this context illustrates a widely applicable principle, that polymorphism in cis-regulatory gene sequences identifies sites where evolution has intervened in the working of the immune system. Where Nature has intervened, the therapeutic strategist would do wise to follow. We believe that comparative genomics, particularly between closely related species such as apes and man, will play an important part in this quest for sites of natural genetic intervention.

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