How Allogeneic Stem Cells are Thought to Be Immune-privileged
The immune system is highly complex. To understand how mesenchymal stem cells (MSCs) interact with it, we should first review some fundamental principles of immune function.
Innate and adaptive immune system
The immune system has two main branches: the innate immune system and the adaptive immune system. The innate immune system is the body’s first line of defense against invading pathogens. It provides a rapid, non-specific response to a wide range of potential threats. Unlike the adaptive immune system, it does not develop memory of previous encounters. It detects pathogens, acts to eliminate the threat, triggers an inflammatory pathway to recruit immune cells and increase blood flow to help clear the pathogen, and presents the antigen to cells within the adaptive immune system to initiate a specific immune response. Some components of the innate immune system include physical barriers like the skin, the mucous membranes which can trap pathogens, stomach acid which can destroy microbes, and white blood cells which can attack foreign cells, trigger allergic reactions, and present foreign antigens.
The adaptive immune system (also known as the acquired immune system) develops in response to antigen exposure. An antigen is something the body recognizes as foreign or non-self, such as parts of pathogens (viruses, bacteria, parasites), allergens, toxins, and cells from another individual. Unlike the innate immune system, which provides a rapid but non-specific response, the adaptive immune system learns and remembers specific pathogens, providing long-lasting immunity.
Major Histocompatibility Complex
The Major Histocompatibility Complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules. MHC molecules are divided into Class I and Class II, each with distinct functions and expression patterns. MHC Class I molecules are present on the surface of almost all nucleated cells in the body. They present endogenous antigens (typically from viruses or intracellular pathogens) to cytotoxic T cells (CD8+ T cells). This allows the immune system to detect and eliminate infected or abnormal cells. MHC Class II molecules are expressed primarily on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells (these cells act as the bridge between the innate and adaptive immune system). They present exogenous antigens (from extracellular pathogens) to helper T cells (CD4+ T cells). This initiates and regulates the immune response, including the activation of B cells to produce antibodies.
How are stem cells “immune-privileged”?
Stem cells express low levels of the major histocompatibility complex (MHC) class I and lack MHC Class II which allows them to be hypoimmunogenic or “immune-privileged.” Since CD8+ T cells rely on MHC I to detect and kill infected or abnormal cells, low MHC I levels on stem cells mean they are less likely to be targeted by the adaptive immune system. However, natural Killer (NK) cells are part of the innate immune system, and they target cells with abnormally low MHC I expression. So, while low MHC I helps avoid T cell detection, it might increase vulnerability to NK cells.1 Because stem cells do not express MHC Class II molecules, they do not actively stimulate helper T cell responses, which reduces the likelihood of initiating an immune response. The immunogenicity may vary amongst MSC types and adipose-derived MSC may be more likely to trigger an immune response in people.2 Although stem cells are thought to be immune privileged, the environment within each individual varies based on disease process and unique immunological state within the patient. Various innate immune cells within the host can contribute to rejection of the MSC treatment, making stem cell therapy less effective.2
Can stem cells trigger a negative immune response?
Depending on the environment they are working in, MSCs can be characterized into two types based on their immunomodulatory properties: the proinflammatory MSC1 type and the anti- inflammatory MSC2 type.2 The pro-inflammatory type has increased expression of several cytokines, microRNA and proteins that activate T cells. The anti-inflammatory type exhibits high expression of bioactive molecules that inhibit T cell activation.2 The different MSC types act as sensors and regulators within inflammatory environments.3 During the initial phase of inflammation, MSC1 may contribute to an appropriate immune response. Conversely, MSC2 can suppress inflammation and immune activation when inflammation becomes excessive.4
Studies in people have found that donor-derived MSCs can rarely trigger immune reactions, specifically when their environment causes them to switch from calming the immune system to activating it.2 The dosage of the administered MSCs does not correlate with the likelihood of an immune reaction in people.2 Numerous clinical studies in humans have demonstrated the safety and feasibility of allogeneic mesenchymal stem cell (MSC) therapy in various diseases, and the risk for a negative reaction is generally thought to be low.2
1. Oh JY, Kim H, Lee HJ, et al. MHC Class I Enables MSCs to Evade NK-Cell–Mediated Cytotoxicity and Exert Immunosuppressive Activity. Stem Cells. 2022;40(9):870-882. doi:10.1093/stmcls/sxac043
2. Li Y, Jin M, Guo D, et al. Unveiling the immunogenicity of allogeneic mesenchymal stromal cells: Challenges and strategies for enhanced therapeutic efficacy. Biomed Pharmacother. 2024;180:117537. doi:10.1016/j.biopha.2024.117537
3. Bernardo ME, Fibbe WE. Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Cell Stem Cell. 2013;13(4):392-402. doi:10.1016/j.stem.2013.09.006
4. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009-1016. doi:10.1038/ni.3002
