Preclinical in vivo assessment of a combination of protein and cell therapies to prevent human islet transplant rejection as a cure for Type 1 diabete

Lead Research Organisation: King's College London
Department Name: Transplantation Immunology & Mucosal Bio

Abstract

Type 1 diabetes (T1DM) is an autoimmune disease in which the beta-cells of the pancreas are destroyed by autoreactive lymphocytes and insulin is no longer produced. The only clinically acceptable treatment for T1DM is insulin replacement by daily injection of the hormone. This treatment makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even, albeit rarely, death. Transplantation of pancreatic islets became an alternative strategy to whole pancreas transplantation due to the advantage of a relatively non invasive technique and to the low risk of surgical complications. However, transplanted islets are subjected to progressive loss, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent need for improvements in islet transplantation. This project, by establishing a new preclinical animal model, will provide novel insights into the mechanisms of human islet graft rejection in vivo and will offer a perfect platform for the development of new therapies in the prevention of islet graft rejection.
We have already demonstrated that: 1. A recombinant cytoprotective protein (APT070) can protect kidney grafts from complement-mediated post-ischaemic damage; 2. In vitro expanded human regulatory T cells (Tregs) can prolong human skin allograft survival in immunodeficient mice reconstituted with PBMC. 3. In a similar model to the one proposed in this project, ex-vivo expanded human Tregs can delay human islet rejection. 4. Complement influences human T cell responses to antigenic stimulation. Indeed APT070 is already in Phase 1 clinical trial in kidney transplantation and adoptive transfer of Tregs has been already applied successfully in bone marrow transplantation to prevent Graft versus Host Disease.
We hypothesize that combining Treg injection with pre-treatment of islets with cytoprotective proteins targeting complement activation will successfully induce indefinite survival of transplanted allogeneic islets. To test this hypothesis, we will 1) further refine the humanised mouse model by using immunodeficient mice transgenic for human MHC molecules; 2) study the immune responses (innate and adaptive) to allogeneic islets in vivo; 3) investigate the therapeutic use of Tregs in combination with the cytoprotective therapeutic protein in preventing rejection of human islets.
The results from the proposed study will provide new insights into establishing the optimal therapy to achieve indefinite survival of islet cells in the cure of Type I diabetes.

Technical Summary

At the end of this project, which tests a strategy for promoting islet survival in a novel pre-clinical model, we should be in a position to translate our findings straight to the clinic. The first major objective is to refine the humanised mouse model already established in our laboratory, so that the results obtained are more representative of those seen in vivo in humans. We will do this by using NSG mice expressing HLA-DR4 molecules but lacking H-2. Once reconstituted with human DR4-expressing CD34+ cells, these mice, which are already available to us, should mount immune responses that are highly similar to those in humans. The second objective is to transplant human islet cells under the kidney capsule (we already have more than one year of experience in this approach) and study the immune responses to the transplanted islets, in particular to define the impact that complement activation has on these responses. The third and final objective will be to expand regulatory T cells by applying protocols that are currently in use in the laboratory and inject these cells in the DR4-NSG mice, in combination with the pre-treatment of islets with complement inhibitor (APT070). Our prediction is that this combination will lead to indefinite islet survival.

Planned Impact

The project proposed in this grant application will benefit patients with type 1 diabetes. If we prove that Treg therapy combined with inhibition of complement activation is successful in the preclinical model proposed here, this therapy can be extended to the clinic. If indefinite survival of transplanted islets can be achieved by the combined therapy, more patients with type 1 diabetes can benefit and less islets will be needed, allowing more patients to benefit from this type of approach.
 
Description MRC project Grant (Co-applicant with G. Lombardi)
Amount £483,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2013 
End 01/2016
 
Description Co-organiser and chair person at Humanised Mouse Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Co-organised and chaired a workshop humanised mouse symposium
Year(s) Of Engagement Activity 2017
 
Description Committee Chair Member- Cost, Galway 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Chair person and participant to discussions at COST, Galway meeting
Year(s) Of Engagement Activity 2016
 
Description ELRIG Research and Innovation conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Regulatory T cell therapy in organ transplantation
Year(s) Of Engagement Activity 2017
 
Description Key note speaker at a conference- 3rd International Molecular and Immunology & Immunogenetics Congress 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled: "Clinical grade manufacture of Regulatory T cells to promote Transplantation Tolerance: Challenges and Achievements."
Year(s) Of Engagement Activity 2016,2017
 
Description Key note speaker at conference- CST-CNTRP-SQT Joint scientific Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "The use of Tregs in Kidney Transplantation."
Year(s) Of Engagement Activity 2016
 
Description Key note speaker to conference- Club de la Transplantation- Lille, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "Immunotherapy after TH, ThRIL Trial
Year(s) Of Engagement Activity 2017
 
Description NIHR in BTRU in ODT 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact interactive workshop involving academics creating a forum to present and share ideas
Year(s) Of Engagement Activity 2017
 
Description key note speaker to conference- Instituo de Medicina Molecular- Lisbon 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled: "Approaching clinical Transplantation tolerance."
Year(s) Of Engagement Activity 2017