Stem cells hold significant promise for regenerative medicine due to their unique ability to self-renew and differentiate into various specialized cell types. A common concern arises regarding how the body’s immune system, designed to detect and eliminate foreign invaders, manages to tolerate these “non-self” cells during transplantation or therapy. Understanding the biological mechanisms that allow stem cells to often avoid immune rejection is important for their successful clinical development.
The Body’s Defense System
The immune system continuously works to distinguish between the body’s own components, known as “self,” and foreign substances, or “non-self.” This distinction is made possible by specific proteins on the surface of nearly all cells, called Human Leukocyte Antigens (HLAs) in humans. These molecules act like identity tags, displaying small fragments of proteins from inside the cell to immune cells, particularly T cells.
If T cells encounter cells displaying foreign protein fragments or MHC/HLA molecules that do not match the body’s own, they initiate an immune response. In the context of organ transplantation, if the donor’s MHC/HLA molecules do not sufficiently match the recipient’s, the immune system recognizes the transplanted organ as foreign. This recognition triggers a robust immune attack, leading to what is known as transplant rejection, where the body attempts to destroy the foreign tissue. Immunosuppressive medications are often required to prevent this rejection in organ transplant recipients.
How Stem Cells Evade Detection
Many types of stem cells, especially mesenchymal stem cells (MSCs) and some pluripotent stem cells, possess unique properties that help them avoid immune detection and rejection. They exhibit low immunogenicity, meaning they are less likely to provoke an immune response. This is partly because they express low levels of MHC Class I molecules and often lack MHC Class II molecules on their surface, making them less visible to T cells.
Stem cells also have immunomodulatory properties, actively influencing the immune system. They secrete various anti-inflammatory and immunosuppressive factors, including cytokines like transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and prostaglandin E2 (PGE2). These molecules can suppress the activity of immune cells such as T-cells, B-cells, and natural killer (NK) cells. Some stem cells can even induce programmed cell death (apoptosis) in activated immune cells that might otherwise target them.
These combined characteristics contribute to a phenomenon known as “immune privilege,” where certain cells or tissues are protected from immune attack. This allows many stem cells to survive and function in a recipient’s body without triggering a severe immune reaction.
Different Stem Cell Sources and Immunity
The origin of stem cells used in therapy significantly influences their potential for immune rejection. Autologous stem cells are those derived from the patient’s own body. Since these cells are genetically identical to the recipient’s cells, they are recognized as “self.” This means they are almost never rejected by the immune system.
Allogeneic stem cells, on the other hand, come from a donor. While they are “non-self” and thus carry different MHC/HLA markers, many types, particularly MSCs, still exhibit their inherent immunomodulatory properties. This allows them to be less likely to trigger a severe rejection compared to solid organ transplants, which typically require intense immunosuppression. In some allogeneic applications, some level of immune matching or mild immunosuppression might still be used.
Induced pluripotent stem cells (iPSCs) are adult cells that have been reprogrammed back into an embryonic-like, pluripotent state. If iPSCs are generated from a patient’s own somatic cells, they offer the same significant advantage as autologous stem cells. They are genetically identical to the patient, meaning that cells derived from these iPSCs would not be recognized as foreign by the patient’s immune system, thereby minimizing the risk of rejection.
When Rejection Can Still Occur
While many stem cells possess properties that help them avoid immune rejection, there are situations where an immune response can still be triggered. A significant factor is differentiation: as stem cells mature and specialize, they may begin to express higher levels of MHC molecules or other tissue-specific antigens. This increased expression makes them more visible to the immune system and potentially susceptible to attack, even if the undifferentiated stem cells were initially tolerated.
The purity of a stem cell preparation also plays a role. Contaminating cells within the stem cell product can be recognized as foreign by the recipient’s immune system, leading to an unwanted immune response. The recipient’s individual immune status, including any underlying autoimmune conditions, can also influence the likelihood and intensity of a rejection response.
In some experimental or clinical contexts, the administration of very high doses or repeated doses of stem cells might, in rare cases, elicit an immune reaction. Researchers actively investigate and manage these factors to ensure the safety and effectiveness of stem cell applications.