Funding opportunities

Mechanisms to protect hESC-derived cells from allogenic immune rejection

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06244
Principle Investigator: 
Funds requested: 
$1 161 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
The potential of human embryonic stem cells (hESC) to differentiate into a tremendous range of biologically active cells/tissues is the basis for many novel therapeutic strategies. However, immune-mediated rejection of hESC-derived tissues by the patient remains a significant barrier to the promise of regenerative therapies. Therefore, it is key to develop strategies to induce immunological tolerance to hESC-derived tissues/cells, thereby inhibiting rejection and evading the risks of routinely used systemic immunosuppressants, including the cytotoxicity and increased risk of infection and cancer. To accomplish this objective, we have expressed proteins known to restrain lymphocyte activity in hESC-derived cells. Importantly, when transplanted into mouse models with functional human immune system, we find that transplanted cells derived from modified hESCs evade rejection and induce sustained immunological tolerance. This is the first time the immune responses to hESC-derived cells have been studied in an in vivo context. Here, we propose to explore the molecular pathways and immune cell types that mediate the induction of immune tolerance and pursue additional targets for further blunting rejection of tissue grafts derived from hESC. To achieve the full potential of hESC-based therapy, it is critical to develop effective approaches to promote long-term immune tolerance of hESC-derived cells, and our studies provide a novel strategy to this end.
Statement of Benefit to California: 
Thousands of Californians receive life-saving tissue transplantation each year. However, the human and medical cost of long-term immunosuppression to promote survival of grafted cells and the limited availability of donor tissues/cells prevents the realization of the full benefits. The potential of human embryonic stem cells (hESC) to differentiate into a tremendous range of biologically active cells/tissues is the basis for many novel therapeutic strategies. However, immune-mediated rejection of hESC-derived tissues remains a significant barrier to the promise of regenerative therapies. Thus, it is key to develop strategies to induce immunological tolerance to hESC-derived tissues/cells, which will allow the clinic realization of the full range of benefits to the health of Californians. We propose a novel approach to promote long-term acceptance of hESC-derived tissues and to better understand the mechanisms of immune tolerance in the context of tissue transplantation. We will focus on the immune tolerance of hESC-derived lung epithelial cells that have been shown to rescue lung functions in animal models, as this cell therapy will save the life of patients with various lung diseases such as the chronic obstructive lung diseases that are major killers in California and pose tremendous burden on medical care in our state. Our research will thus lead to important progress in stem cell therapies to better meet the needs of Californians.
Review Summary: 
The overall objective of the proposal is to develop strategies that prevent immune mediated rejection of human embryonic stem cell (hESC) derived cells and tissues. The applicant has generated genetically modified hESCs expressing immune modulatory factors that are not rejected following transplant into an immunocompetent preclinical model. In this proposal, the applicant intends to investigate this tolerance mechanism in order to identify potential approaches that will enable survival of differentiated hESC-derivatives in an allogeneic host, without need for immunosuppressive drugs. The applicant proposes to identify the immune cells responsible for rejection of hESCs and investigate the mechanisms for tolerance of the genetically modified hESCs and the individual and combinatory contributions of each immune modulatory factor on the observed tolerance. Additionally, the applicants intend to build on their initial findings by modifying hESC-derived cells using different immune modulatory factors, identifying which of these additional factors can mediate tolerance to hESCs and their derivatives, and to engineer these cells such that they can be eliminated using FDA-approved drugs should they escape immune detection and become tumorigenic following therapeutic administration. Significance and Innovation - The proposal aims to address a significant bottleneck in translating pluripotent stem cell-based cellular therapies: overcoming the need for immunosuppressive drugs for allogeneic cell transplantation. If successful, this would increase the potential reach of cellular therapies by decreasing the undesirable side effects of generalized immune suppression. - Arming hESC-derived cells and tissues with immune modulatory factors is an innovative approach to aid allogeneic graft acceptance. Feasibility and Experimental Design - The experimental design is feasible and addresses an important question. However, the primary flaw of this proposal is that most of the studies are investigating tolerance exhibited to hESC populations, which are teratogenic and would not be therapeutically transplanted. Further, it is not clear that tolerance to teratomas, which are capable of evading immune detection, will extend to other, differentiated cell types. - Though study of immune tolerance to a differentiated cell type is of far greater importance than study of tolerance to hESC populations, study of only one differentiated cell type is proposed and selection of that particular cell type is poorly justified. - Applicants have underestimated the challenges in the differentiation of hESCs to the differentiated cell type proposed in the study. Moreover, it is not clear that the proposed cell population can successfully engraft and survive in the murine model. Since this is the most important aspect of the study, this weakness should be addressed by engaging an expert in this field if the proposal receives funding. -- The third aim of the proposal was considered overly broad, and it was not clear how the applicant would prioritize the findings. Further, the element of this aim focused on engineering an hESC that could be eliminated using an FDA-approved drug was deemed tangential to the project and well studied by other investigators. - The scientific rationale is reasonable and the preliminary data support the feasibility of completing the proposed studies. - The study takes advantage of state-of-the-art murine models and should provide informative results. However, there was some concern that some of the secreted immunomodulatory factors proposed in the study may result in global immunosuppression - Proposed mechanistic studies were judged to be descriptive and lacking details on the methodologies, and the definition of tolerance put forth by the applicant appeared to be too loose. Principal Investigator (PI) and Research Team - The PI is an outstanding expert in immunology and is well qualified to direct immunological aspects of the proposed work. - The Co-Investigator brings complementary expertise and strength in hESC biology to the project. - Reviewers encouraged the PI to add a collaborator with expertise in differentiating hESCs to the proposed differentiated cell type to strengthen the project’s feasibility Responsiveness to the RFA - The proposed research is responsive to the RFA, as it focuses on human stem cells and basic mechanism of tolerogenicity and immunogenicity, an area of focus in the RFA. Reviewers noted that this focus on such an important element of the RFA was a key strength of the proposal that increased their overall enthusiasm for the project.
Programmatic review: 
  • PROGRAMMATIC DISCUSSION
  • A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers noted that if funded, this would be the only project addressing immune tolerance of hESC-derived cells/tissues, something the panel considered an important element of the RFA. The panel thought that Aim 3 is tangential to the project and should be eliminated and all the requested funds should be used to accomplish aims 1 and 2. The reviewers noted that the significant design flaws (the focus on tolerance to hESC populations rather than differentiated cell populations) and feasibility concerns (the lack of expertise of the PI in generating the described differentiated cell type) were addressable by the applicant. The motion carried with the recommendation that Aim 3 be removed from the project.
Conflicts: 

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