Final Report Summary - TREG SUPPRESSION (Deciphering the molecular basis of regulatory T cell suppression)
After my postdoctoral studies in US I returned to Sweden to set up my own research group. The Marie Curie FP7 reintegration grant was the first external grant I received and it has been invaluable for the work of my research group over the last 4 years. Below is a brief summary of my/our progress:
BUILDING A RESEARCH GROUP
A key aspect to the feasibility of this project has been to attract additional funding to that one contributed by EU. I am happy to say that the project now is backed by the three most influential grant agencies in Sweden including the Swedish Research Council, the Swedish Cancer Foundation and the Swedish Heart-Lung Foundation as well as several private foundations. The total amount of the awarded grants is approximately 2 million Euros. This has allowed me to build a research group, which currently consists of two postdoctoral fellows and one PhD student. I see no reason why we should not be able to continue to thrive and I have recently received further support from Karolinska Institutet to ensure that I can establish a career here.
PERFORMING THE PROPOSED RESEARCH
Our research concerns the regulation of the immune system. The immune system is the body's defense against infectious organisms. It is delicately regulated to allow responses against foreign- but not self-antigens. Therapeutical strategies aimed at modifying immunological tolerance and thus the strength and nature of an immune response have tremendous clinical potential in inflammatory disorders and cancer. One component contributing to immunological tolerance is CD4+FoxP3+ regulatory T (Treg) cells, which comprise a subset of T cells that suppress immune activation in a dominant manner. Many aspects of Treg cell biology have been extensively studied but the molecular changes in cells that are being suppressed by Treg cells remain almost completely uncharacterized.
We have previously demonstrated that TReg cells have the capability to induce FoxP3 expression in naïve T cells in a TGF-beta-dependent, cell contact-dependent manner This transfer of suppressive activity from one population of cells to another is known as infectious tolerance. Infectious tolerance is dependent on cell surface bound TGF-beta on TReg cells and while several questions remain about the TGF-beta‘s regulation we have now proven that the protein GARP (LRRC32) tethers latent TGF-beta to the cell surface. After realizing that TGF-beta is specifically expressed on activated TReg cells we also exploited this finding to develop a strategy to isolate human TReg cells. In a related study we extended these studies on TGF-beta’s role in disease and generated mice with a T-cell specific deletion of Smad7, a potent inhibitor of TGF-beta signaling that acts downstream of the TGF-beta receptor. Smad7-deficient mice develop atherosclerotic lesions with a smooth muscle cap through an IL-17 dependent mechanism. These plaques may be less vulnerable to rupture and thus affecting the propensity for thrombus formation and the clinical outcome of disease in a beneficial manner. ]. De novo generation of TReg cells can also be accomplished in other manners and we demonstrated that through adoptive transfer of IL-10 treated dendritic cells results increased numbers of TReg cells a significant reduction of atherosclerotic lesions in the aorta
INITIATING RESEARCH COLLABORATIONS WITH INDUSTRY
The aim of my research is to contribute to understanding how Treg cells can be targeted/used in a clinical setting. However, results obtained from academic research can be difficult to exploit from a commercial/clinical perspective without the appropriate support. Therefore I have made a made a conscious effort to establish collaborations with companies interested in T cell immunology for either diagnostic and/or treatment purposes. I believe that these collaborations have strengthened the overall research done by my group and that it has been well-invested time. Examples of activities aimed at creating industry collaborations include:
1) Acting as scientific advisor for KaroBio, Sweden (www.karobio.com) when evaluating nuclear receptors as targets to modulate Treg cell function.
2) Initiating collaboration with Almac, Northern Ireland (www.almacgroup.com) to determine the value of Treg markers cells in cancer diagnostics.
3) Successfully applying for a commercialization from Vinnova/Karolinska Institutet.
4) Filing for one patent regarding how to inhibit Treg cell function to amplify anti-cancer immune responses.
ESTABLISHING RESEARCH COLLABORATIONS WITH CLINICS
Over the last 6 months we have initiated collaboration with Olle Korsgren’s group at Uppsala University. The work here aims at treating patients suffering from inflammatory disorders with adaptive transfer of regulatory T cells. Our part in this collaboration is to characterize the cells
previous to infusion in regards to their phenotype. The first patients will be treated at the end of the year and it will be among the first clinical studies regarding regulatory T cell therapies. If these trails are successful they could have a substantial socio-economic impact.
BUILDING A RESEARCH GROUP
A key aspect to the feasibility of this project has been to attract additional funding to that one contributed by EU. I am happy to say that the project now is backed by the three most influential grant agencies in Sweden including the Swedish Research Council, the Swedish Cancer Foundation and the Swedish Heart-Lung Foundation as well as several private foundations. The total amount of the awarded grants is approximately 2 million Euros. This has allowed me to build a research group, which currently consists of two postdoctoral fellows and one PhD student. I see no reason why we should not be able to continue to thrive and I have recently received further support from Karolinska Institutet to ensure that I can establish a career here.
PERFORMING THE PROPOSED RESEARCH
Our research concerns the regulation of the immune system. The immune system is the body's defense against infectious organisms. It is delicately regulated to allow responses against foreign- but not self-antigens. Therapeutical strategies aimed at modifying immunological tolerance and thus the strength and nature of an immune response have tremendous clinical potential in inflammatory disorders and cancer. One component contributing to immunological tolerance is CD4+FoxP3+ regulatory T (Treg) cells, which comprise a subset of T cells that suppress immune activation in a dominant manner. Many aspects of Treg cell biology have been extensively studied but the molecular changes in cells that are being suppressed by Treg cells remain almost completely uncharacterized.
We have previously demonstrated that TReg cells have the capability to induce FoxP3 expression in naïve T cells in a TGF-beta-dependent, cell contact-dependent manner This transfer of suppressive activity from one population of cells to another is known as infectious tolerance. Infectious tolerance is dependent on cell surface bound TGF-beta on TReg cells and while several questions remain about the TGF-beta‘s regulation we have now proven that the protein GARP (LRRC32) tethers latent TGF-beta to the cell surface. After realizing that TGF-beta is specifically expressed on activated TReg cells we also exploited this finding to develop a strategy to isolate human TReg cells. In a related study we extended these studies on TGF-beta’s role in disease and generated mice with a T-cell specific deletion of Smad7, a potent inhibitor of TGF-beta signaling that acts downstream of the TGF-beta receptor. Smad7-deficient mice develop atherosclerotic lesions with a smooth muscle cap through an IL-17 dependent mechanism. These plaques may be less vulnerable to rupture and thus affecting the propensity for thrombus formation and the clinical outcome of disease in a beneficial manner. ]. De novo generation of TReg cells can also be accomplished in other manners and we demonstrated that through adoptive transfer of IL-10 treated dendritic cells results increased numbers of TReg cells a significant reduction of atherosclerotic lesions in the aorta
INITIATING RESEARCH COLLABORATIONS WITH INDUSTRY
The aim of my research is to contribute to understanding how Treg cells can be targeted/used in a clinical setting. However, results obtained from academic research can be difficult to exploit from a commercial/clinical perspective without the appropriate support. Therefore I have made a made a conscious effort to establish collaborations with companies interested in T cell immunology for either diagnostic and/or treatment purposes. I believe that these collaborations have strengthened the overall research done by my group and that it has been well-invested time. Examples of activities aimed at creating industry collaborations include:
1) Acting as scientific advisor for KaroBio, Sweden (www.karobio.com) when evaluating nuclear receptors as targets to modulate Treg cell function.
2) Initiating collaboration with Almac, Northern Ireland (www.almacgroup.com) to determine the value of Treg markers cells in cancer diagnostics.
3) Successfully applying for a commercialization from Vinnova/Karolinska Institutet.
4) Filing for one patent regarding how to inhibit Treg cell function to amplify anti-cancer immune responses.
ESTABLISHING RESEARCH COLLABORATIONS WITH CLINICS
Over the last 6 months we have initiated collaboration with Olle Korsgren’s group at Uppsala University. The work here aims at treating patients suffering from inflammatory disorders with adaptive transfer of regulatory T cells. Our part in this collaboration is to characterize the cells
previous to infusion in regards to their phenotype. The first patients will be treated at the end of the year and it will be among the first clinical studies regarding regulatory T cell therapies. If these trails are successful they could have a substantial socio-economic impact.