Developing FAS-Resistant, Bone Marrow-Tropic Regulatory T Cells (Tregs) for the Treatment of Immune Aplastic Anemia
Abstract
Aplastic anemia (AA) is a rare and severe disorder and can affect any age group but with a biphasic peak incidence in young adults and patients aged over 60 years. The immune system plays an essential role in AA and specific immune cells, known as T cells, attack specialized cells in the bone marrow, which could differentiate into blood cells, causing a significant reduction in all types of blood elements which are red blood cells, white blood cells, and platelets. The most common symptoms of AA are anemia (low number of red blood cells), which causes fatigue, shortness of breath or headaches, and an increased risk of infections due to low white blood cells. Additionally, low platelets may lead to bleedings which could be life-threatening. Being more susceptible to severe and life-threatening infection and bleeding complications makes AA a hazardous disorder and may lead to extreme medical conditions and even death. Although AA patients respond very well to current therapies such as immunosuppression or bone marrow transplantation, some patients do not respond to these therapies or do not have bone marrow donors. Therefore, novel therapies with fewer side effects are necessary for AA. We and others have shown that an important regulatory mechanism of the immune system is not functioning properly in AA. One of the main reasons for that is the low number of other specialized type of immune cells, known as regulatory T cells or Tregs. The function of Tregs is to dampen down the abnormal immune-attacking cells that destroy bone marrow stem cells. Using a specific culture environment, we have successfully expanded these cells from AA patients to the level which could potentially be used therapeutically. We have also shown that these cells are functional after expansion and prevent self-attack, similar to AA in a mouse model. The limitation, however, is the low Treg number in AA, which makes it challenging to expand enough Tregs for conventional cell therapy as utilized in other diseases such as type 1 diabetes. This remains a barrier to effective cell therapy in AA. We propose overcoming this limitation by engineering Tregs to make them resistant to early cell death in the inflammatory environment and enhance their recirculation to bone marrow, allowing a far smaller number of Tregs to be effectively targeted to this environment. This goal will be achieved by genetic modification of Tregs to reduce the cell death receptor expression (known as Fas) and to target the Treg population to the diseased bone marrow. We would also like to optimize the current mouse model to test the function and longevity of these Tregs in a hostile and inflammatory environment. The innovation comes from delivering the key cell to the key location type while enriching suppressive capability through protecting against cell death. This project could lead to a novel treatment with engineered Tregs to control autoimmunity with fewer bone marrow-targeted Tregs. The potential advantages of using Tregs are that they are expected to cause less infection than immunosuppression therapy and offer a new treatment option for those patients who are not eligible for bone marrow transplantation or do not have a donor. In the future, this approach could also be used in other immune-related conditions such as graft versus host disease after bone marrow transplantation as well as other autoimmune disorders to direct shielded Tregs to the point of inflammation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211097
Entities
People
- Shahram Kordasti
Organizations
- United States Army