Transplantation is widely recognized as the treatment of choice for end-stage organ disease in children. Nevertheless, despite significant advances in immunosuppressive therapeutics to prevent acute rejection, long-term graft survival remains suboptimal. It has therefore become most apparent that success following transplantation will require greater understanding of responses that both promote and inhibit chronic allograft rejection. There is also a huge need to develop mechanistic biomarkers to define the status of the alloimmune response, as well as indices of graft injury as a transformative care initiative to optimize therapy post transplantation.

Research in the Briscoe Laboratory relates to all these issues with a focus on the intragraft microenvironment, and how it functions to both promote and inhibit chronic rejection. Our studies focus on three broad areas including: 1) how events within the intragraft microenvironment including leukocyte-endothelial cell interactions promote, sustain, or inhibit T cell activation and allorecognition; 2) discrete signals and molecular interactions in select populations of T cells that are integral to inflammation resolution; and 3) the application of these discoveries into the development of biomarkers and new therapeutics to transform clinical care and improve outcomes following transplantation.

 

Active projects include:

 

1. Novel regulatory molecules within T cells: Allograft rejection is mediated by the recipient’s immunological response to donor antigen, initiated and coordinated by CD4+ T cells. Once T cells encounter alloantigen, they undergo expansion and differentiation into effectors and/or memory T cells. However, activation also results in the expansion of regulatory T cells that function to control the immune response, and it is proposed that this process of immunoregulation is critical for long-term allograft survival. Within T cells, several adapter proteins including TSAd have been found to be active participants in signaling responses that modulate T cell activation and immunoregulation. We find that the relative activity of TSAd is critical for T regulatory cell activation, and we reported that its absence is associated with resistance to costimulatory blockade in vivo. Our hypothesis is that manipulation of select adaptors alters T effector-T regulatory cell interactions and transplant rejection.

 

2. DEPTOR/mTOR interactions: This research project is based on the observation that Akt-mTOR signaling is potent to mediate activation and proliferative responses in many immune cell types. However, several cell-intrinsic negative regulators of mTOR activity also function to suppress these responses. We have developed in vitro and in vivo model systems to address questions about endogenous regulators of mTOR and we are testing if they are functional to inhibit allograft rejection as well as other forms of T cell-dependent inflammation in vivo. One such molecule, DEPTOR, is the focus of multiple ongoing studies. In CD4+ T cells, its level of expression is important for the overall immunomodulatory function of T regulatory cells. Specifically, high intrinsic DEPTOR levels are associated with Treg stability and function. In addition, in ongoing studies, we have found that its level of expression within endothelial cells is also of significance to dictate local degrees of inflammation. For example, we find that reduced levels of DEPTOR are associated with marked endothelial activation responses. Our overall hypothesis is that augmentation of the activity of endogenous cell-intrinsic DEPTOR will sustain anti-inflammation and promote tolerance following transplantation.

 

3. Semaphorins and immunoregulation: Another project within the laboratory focuses on the interactions between semaphorins, VEGF and the neuropilin family of molecules. This project is based on initial observations in which we reported that the binding of semaphorin-3F to neuropilin-2 results in the inhibition of Akt and mTOR activity. Thus, neuropilin-2-dependant signaling in select immune cell types is likely of great significance as a component of the inflammation resolution pathway. In our ongoing studies, we have developed novel transgenic mice for the analysis of neuropilin-2 dependant biology in transplant rejection.

 

4. Clinical trial initiatives: There is a great need to study unique alloimmune, genomic, and age-specific biology in pediatric patients following renal transplantation. For many years, Dr. Briscoe’s laboratory has developed and validated biomarkers to identify transplant recipients at risk of acute or chronic rejection. The laboratory has also had a long-standing involvement in innovative clinical trials that include advanced mechanistic studies and biomarker use to evaluate efficacy of novel therapeutics. Currently, Dr. Briscoe is the Principal Investigator of a consortium U01 grant to evaluate the therapeutic efficacy of costimulatory blockade therapeutics following pediatric renal transplantation. Planned collaborative studies will be performed in multiple sites within the US to evaluate the targeting of both cellular and humoral alloimmune responses, immunoregulation as well as pathogen-specific and protective immune responses in trial recipients.