Study reveals immune response mechanism to hiPS-CM sheets in treating ischemic heart disease

New Delhi: In a study, researchers from Juntendo University have elucidated the immune response mechanism against human-induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) sheets, shedding light on potential barriers and solutions for clinical applications.

Published in The Journal of Heart and Lung Transplantation, the research explores how CD8+ T cells orchestrate the rejection of these therapeutic sheets, critical for treating ischemic heart disease.

Ischemic heart disease, a leading cause of global morbidity and mortality, has spurred interest in hiPS-CMs as a promising treatment option. These cells, derived from adult somatic cells like blood or skin cells, possess the capacity to differentiate into various tissues, including cardiomyocytes and hold the potential for repairing damaged heart tissue. However, concerns about immune rejection have limited their clinical viability.

Led by PhD student Ryu Matsumoto, with co-leaders Assistant Professor Yin Enzhi and Associate Professor Koichiro Uchida from Juntendo University’s Center for Immune Therapeutics and Diagnosis at Juntendo University Graduate School of Medicine, Tokyo, Japan, the research team developed a unique humanized mouse model to mimic immune responses to hiPS-CMs. Known as hPBMC-NOG-ΔMHC mice, this model involves genetic modifications that suppress major histocompatibility complex (MHC) expression, crucial for minimizing immune rejection of transplanted human cells. Their findings were published online on April 22, 2024, in The Journal of Heart and Lung Transplantation.

Explaining the motivation behind the present research, Matsumoto says, “Being a surgeon, I am highly aware of the critical shortage of donor hearts for patients with advanced cardiovascular disease. Although transplantation of hiPS-CM sheets could be a novel therapeutic option, the issue of immune rejection against these sheets poses a significant barrier to their clinical safety and efficacy. Therefore, a humanized mouse model could be a valuable tool to predict and understand this immunological rejection, paving the way for safer and more effective transplantation procedures involving hiPS-CM sheets.” The team began by engineering the hPBMC-NOG-ΔMHC mice through rigorous genetic modifications and precise experimental procedures.

The NOG-ΔMHC mice are developed by merging the immunodeficient properties of NOG mice with a critical alteration: the removal of major histocompatibility complex (MHC) class I and class II expression. This genetic modification is essential in minimizing the risk of immune rejection of transplanted human cells, thus facilitating more effective research into cell-based therapies. The researchers then “humanized” these immunodeficient mice by introducing human peripheral blood mononuclear cells (hPBMCs). This innovative technique enhances the model’s relevance for studying human immune responses and evaluating therapeutic strategies involving human cell transplants.

In vitro experiments revealed that hiPS-CM sheets express human leukocyte antigen (HLA) class I molecules, triggering a moderate immune response. However, transplantation into hPBMC-NOG-ΔMHC mice resulted in rejection within 17 to 24 days, primarily driven by CD8+ T cells. These immune cells infiltrated the graft site and produced elevated levels of interferon-gamma (IFN-γ), a key immune signaling molecule.

Notably, this immune-mediated rejection did not occur without the transfer of hPBMCs into the mice, highlighting the essential role of these immune cells in initiating an anti-graft response. The study underscored the pivotal role of CD8+ T cells in mediating immune rejection. It showed that depleting CD8+ T cells or administering tacrolimus, an immunosuppressive drug, significantly extended the survival of hiPS-CM sheets in the hPBMC-NOG-ΔMHC mice.

Dr. Matsumoto emphasized the study’s implications for clinical practice, suggesting, “Our research paves the way for developing optimal immunosuppression strategies, potentially making hiPS-CM sheets transplant a reality for many patients with severe heart failure in the near future.”

This study uncovers the role of CD8+ T cells and the mechanisms behind the rejection of human iPS-derived cell products. By focusing on patient-specific approaches and carefully considering immunosuppressive strategies, hiPS-CM sheet transplants could potentially become a life-saving treatment for individuals with end-stage heart failure.