Stem cells are undifferentiated cells with the potential to self-renew and develop into specialized cell types. This capacity makes them the foundation of regenerative medicine, offering the promise of repairing tissues damaged by disease or injury. When foreign material, such as an organ transplant, is introduced, the immune system is programmed to detect and destroy it. The central question in stem cell therapy is how transplanted cells survive without triggering the destructive immune response that rejects other foreign tissues. The answer involves the cell source and specific biological features inherent to certain stem cell types.
The Standard Immune Response to Foreign Tissue
The body’s natural defense system uses a molecular identification system to distinguish between “self” and “non-self.” This identity check is primarily governed by proteins known as Human Leukocyte Antigens (HLA), or the Major Histocompatibility Complex (MHC). These HLA molecules sit on the surface of almost every cell, displaying small protein fragments. When a T-cell encounters a foreign HLA protein, it recognizes the cell as non-self and initiates a powerful immune reaction.
If transplanted tissue lacks matching HLA markers, the recipient’s T-cells become activated through allorecognition. This activation triggers an acute rejection response, leading to the release of pro-inflammatory signaling molecules like cytokines. These molecules recruit other immune cells, including cytotoxic T-cells and natural killer (NK) cells, to destroy the transplanted cells. This inflammatory cascade causes massive cell death and tissue necrosis, defining graft rejection.
The Source Matters: Autologous Versus Allogeneic Stem Cells
The origin of stem cells dictates the fundamental risk of an immune reaction. Transplants are categorized based on whether the cells come from the patient (autologous) or a donor (allogeneic). Autologous stem cells, harvested from the patient’s own body and reintroduced, carry virtually no risk of immune rejection. Since they carry the patient’s exact HLA markers, the immune system recognizes them as “self” and allows integration.
This personalized approach bypasses the need for intensive immunosuppressive medication and eliminates the risk of graft-versus-host disease (GVHD). However, this method is not always feasible, especially if the patient’s own cells are compromised or non-viable. When cells are needed from an external source, the transplant is classified as allogeneic.
Allogeneic stem cells are inherently foreign and face a high risk of rejection by the recipient’s immune system. To prevent graft destruction, the body’s defense mechanisms must be actively managed. For these donor cells to survive, the recipient’s immune system must be suppressed, or the cells must possess special properties to avoid immune detection.
Cellular Mechanisms for Immune Evasion
Certain allogeneic stem cells, particularly mesenchymal stem cells (MSCs), are “immune-privileged,” actively evading the host’s defenses. A significant mechanism is the low or absent expression of key recognition molecules on their surface. MSCs often express very low levels of MHC Class I and generally lack MHC Class II molecules, making them poor targets for direct T-cell recognition.
The absence of MHC Class II is important because it prevents the active stimulation of T-helper cells, which coordinate robust immune responses. Although low MHC expression helps avoid cytotoxic T-cells, it can make them vulnerable to natural killer (NK) cells, which target cells with abnormally low MHC levels. MSCs counteract this vulnerability by secreting molecules that actively suppress NK cells.
These cells are also potent immunomodulators, actively signaling the immune system to stand down. They achieve this by secreting suppressive signaling molecules, such as the cytokines Transforming Growth Factor-beta (TGF-beta) and Interleukin-10 (IL-10). These factors inhibit T-cell proliferation and interfere with the function of other immune cells, creating a localized anti-inflammatory environment. Furthermore, many stem cells produce the enzyme indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan necessary for T-cell activation.
Clinical Strategies to Ensure Engraftment
When using allogeneic stem cells, medical intervention is necessary to support engraftment, especially in high-risk procedures like hematopoietic stem cell transplantation. The primary clinical strategy is meticulous HLA matching between the donor and the recipient, which significantly reduces genetic disparity. Since finding a perfectly matched donor is rare, clinicians often rely on a spectrum of matches to proceed.
Before the transplant, a conditioning regimen is performed to prepare the patient’s body to accept the foreign cells. This regimen typically involves high-dose chemotherapy and sometimes radiation. It serves two primary purposes: eliminating the patient’s diseased cells and suppressing their immune system. Conditioning regimens range from myeloablative, which completely destroys the host bone marrow, to reduced-intensity, which is less toxic and relies more on immune suppression.
Following conditioning and infusion, the recipient is often given powerful immunosuppressive drugs. Medications like cyclosporine, fludarabine, and methotrexate prevent remaining T-cells from attacking the foreign graft. This strategy requires a delicate balance: the drugs must prevent rejection and GVHD without leaving the patient vulnerable to severe infections. The overall goal is to create a window of opportunity for donor cells to settle in and begin producing new, healthy blood and immune cells.