SUMMARY
The research of Mohsen Khosravi Maharlooei focuses on immunoengineering. Dr. Khosravi develops and applies novel ways of inducing immune tolerance. He uses integrated approaches that combine laboratory, clinical and computational methods.
Engineering of immune cells such as regulatory T cells called Tregs and hematopoietic stem cells called HSCs are an integral part of these novel methods. Engineering approaches such as CRISPR and viral transduction are implemented to engineer the immune cells.
Novel discovery methods such as CRISPR screening are employed to identify new target genes. Transcriptomics, epigenomics and proteomics data analysis are implemented to evaluate immune cells from clinical samples, humanized mice and in vitro assays.
Focus areas
- Dissecting the mechanisms and signaling events underlying the development and plasticity of human thymic-derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). Despite profound advancements, major questions remain unanswered regarding the development, plasticity and function of human Tregs. Humanized mice provide access to Tregs in different organs and allow manipulation of different factors. The research of Dr. Khosravi exploits the tools that this model provides, in addition to the state-of-the-art technologies to study the factors involved in the development and plasticity of Tregs. Understanding the molecular events underlying these processes can identify therapeutic targets for transplantation, autoimmunity, graft versus host disease and even cancer.
- Development of next-generation Chimeric Antigen Receptor (CAR) Tregs for transplantation, xenotransplantation and autoimmunity. Controlling immune responses in transplantation and autoimmunity is a major health challenge. Despite promising results in using CAR Tregs for controlling antigen-specific immune responses, there are major considerations regarding the plasticity of CAR Tregs.
There are questions about the effect of conditioning regimens and immunosuppressive medicines on CAR Tregs that need to be addressed before they are clinically applied. Dr. Khosravi's research employs a combination of genetic engineering approaches to generate conversion/conditioning-resistant CAR Tregs.
These CAR Tregs have enhanced capabilities for controlling immune responses in transplantation, xenotransplantation and autoimmunity.
- Analyzing the signaling and metabolic defects of Tregs in human autoimmune diseases and applying genetic engineering approaches to correct the defects for autologous Treg therapies. It has been suggested that an inherent defect in regulatory T cells (Tregs) and the presence of inflammatory cytokines in inflamed tissues leads to plasticity of Tregs. This inflammation and their conversion to effector T cells (Teff) leads to development of autoimmune diseases such as psoriatic arthritis.
The research of Dr. Khosravi evaluates Tregs from peripheral blood and affected tissues of autoimmune patients in comparison to the ones from healthy controls to identify these defects.
Additionally, the lab will apply genetic modifications to increase the stability of Tregs from autoimmune patients and evaluate its efficacy in humanized mouse models. This could be a potential cell therapy approach for treating autoimmune diseases such as psoriatic arthritis.
- Engineering of human hematopoietic stem cells (HSCs) for induction of immune tolerance through autologous HSC transplantation. Autologous HSC transplantation has been used as a therapy for autoimmune diseases. However, as the genes and human leukocyte antigens (HLAs) predisposing to autoimmunity are still present in autologous HSCs, Dr. Khosravi's research will genetically engineer the HSCs ex vivo to modify the predisposing genes and HLAs before transplanting them back to the patients.
This therapy will be tested in humanized mouse models of autoimmunity. These studies will provide unprecedented insight into the mechanisms of development of autoimmunity and the role of predisposing genes and HLAs. Similar approaches will be implemented to induce immune tolerance in allo and xenotransplantation.
- Investigating mechanisms of lymphopenia-induced proliferation (LIP) of T cells, interaction of T cells undergoing LIP with antigen-presenting cells (APCs) and ways to prevent autoimmunity in patients experiencing lymphopenia.For two decades, it has been known that T cells undergo proliferation in the absence of cognate antigens and their phenotype converts from naïve to memory in a lymphopenic environment.
It has been speculated that lymphopenia-induced proliferation of T cells leads to the development of autoimmunity. Using humanized mouse models, Dr. Khosravi has acquired direct evidence for the contribution of LIP in the facilitation of autoimmunity.
His research will characterize the downstream signaling pathways that are turned on in T cells undergoing LIP and find out how they are different compared to the T cells getting activated through their cognate antigens. Additionally, engineering approaches to prevent LIP-induced autoimmunity will be investigated.
Significance to patient care
There is a need for a safer and more effective immunosuppressive therapy for transplantation and autoimmunity. For transplantation, improved and targeted immunosuppressive therapy could reduce the risk of organ rejection and side effects from general immunosuppression.
Transplant recipients require a lifelong regimen of powerful immunosuppressive therapies that are not only expensive, but come with risks. In addition, despite these therapies, 40% to 70% of patients reject their organ by year 10 after transplantation. In 2019, 7% of the adult population in the United States had autoimmune diseases. Dr. Khosravi's research focuses on developing cell therapy approaches that obviate or reduce the need for immunosuppressive medications in transplantation and autoimmunity.