Highlight Publication March 2010

Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JSH, Tasken K, Bunyard P, Okkenhaug K (2010)
PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
Blood 115 2203-2213
http://dx.doi.org/10.1182/blood-2009-07-232330

Lay description

The immune system has very powerful tools at its disposal, enabling it to rid the body of infections. However, in susceptible individuals, these same tools can be unleashed in the absence of infection and can lead to autoimmunity, allergies, or asthma. Strategies to dampen the immune response without affecting other organs or systems could be helpful in treatment of these conditions. Chronically activated memory T cells can orchestrate immune responses and their suppression would be predicted to have beneficial effects in these diseases.

PI3K p110δ is an enzyme found almost exclusively in cells of the immune system and which has been shown to control many immune functions. Hence, there is real excitement about inhibiting PI3K p110δ to treat diseases of the immune system without affecting other organ functions. Indeed, such inhibitors have recently entered Phase I clinical trials for autoimmune arthritis and leukaemia.

Most of what we know about PI3K p110δ has been garnered from studies in mice. While these animals are experimentally tractable and useful for pre-clinical models, their immune systems differ to some degree from humans. Hence it is useful to do side-by-side comparisons of how mouse and human T cells respond to p110δ inhibition. To this end, we examined how a prototype PI3K p110δ inhibitor affected activation of both mouse and human T cells.

We found that inhibiting PI3K p110δ reduced the amount of inflammatory cytokines produced by previously activated and memory T cells in mice and humans. The same effects were seen when T cells came from humans reacting to an allergen or from the joints of inflammatory arthritis patients. In a mouse model of a contact allergy, administration of a PI3K p110δ inhibitor could reduce inflammation even after the reaction had begun.  From these studies, we conclude that inhibiting PI3K p110δ may have a positive effect in T cell-driven diseases of the immune system and that the mouse is a valid model to further understand the molecular mechanisms.

These studies were done with the help of the Jonathan Clark of Babrabraham Bioscience Technologies who synthesised an inhibitor used in these studies. We also collaborated with Professor Tasken’ sgroup in Norway who analysed signalling networks in human  T cells perturbed by p110δ inhibition. The work also involved  an industrial collaboration with UCB, who funded a studentship and provided facilities to do studies with human  T cells, and with a clinical collaboration with Professor Hill Gaston of Addenbrooke’s Hospital, who provided biopsies from patients with Arthritis .

About the lead author

Dalya Soond received a M.Sc. in 2001 from the University of Colorado Health Sciences Center for work assessing how apoptotic cells are removed from the body. She obtained a Ph.D. in 2009 for work done in Klaus Okkenhaug’s lab studying the role of the Pten tumour suppressor and PI3K p110δ in T cells and possible translational applications. Dalya has remained on as a post-doctoral scientist in the Okkenhaug lab to study the roles of Pten and PI3K p110δ in memory T cell functions and tumour surveillance.