Human aging is a complex physiological process, accompanied by the occurrence of aging-related diseases, such as cancer, II diabetes, autoimmune diseases, infections, cardiovascular and cerebrovascular diseases, etc. One of the main causative factors is immune decline.
The decline of the immune system weakens the body's resistance to tumors and pathogens and increases the risk of autoimmunity And cause a chronic inflammatory state. In the past ten years, the number of people over 65 years old in developed countries has increased by more than 10%, and is expected to exceed 20% in 2030.
Immune cell technology has a significant role in clearing senescent cells and treating malignant tumors, and is a major contributor to aging-related diseases. Provides effective methods for prevention and treatment.
Aging is a complex phenomenon characterized by progressive decline in physiological functions and tissue homeostasis. , leading to an increased incidence of degenerative diseases and death. There are many theories about aging, including genetic theory, cell mutation theory, free radical theory, and neuroendocrine theory. In recent years, many scholars have noticed the relationship between immunity and aging and proposed the immune theory of aging.
Aging shows obvious changes at the cellular and systemic levels of the body. Aging at the cellular level is characterized by cell cycle arrest of dividing cells, and various forms of cell damage or stress can induce cellular senescence. In addition, senescent cells usually downregulate proliferation-related genes and highly express inflammatory factors and other molecules that regulate immune responses [1-2]. The most obvious phenomenon caused by aging is the imbalance of the immune system, including immune decline and chronic inflammation [3-4]. The decline of the immune system reduces immune protection against tumor cells and pathogens, while chronic inflammatory states increase the risk of autoimmune diseases [5-6].
Therefore, human aging is manifested by an increased incidence of aging-related diseases, such as tumors and metabolic syndrome , autoimmune diseases, infections, cardiovascular and cerebrovascular diseases and neurodegenerative diseases [3]. Therefore, some people call aging an epidemic immune disease.
Immune system and aging
The innate immune system is the body’s first defense mechanism, and the acquired immune system is a specific immune response against antigens [7]. Like most biological processes, aging affects both the adaptive and innate immune systems [8-10]. The aging of the immune system is a multifactorial cascade event, and different types of immune cells show different sensitivities. It is worth noting that there are also gender differences in immune decline [11].
Thymus and Aging
The thymus is a central T lymphoid organ that produces functional initial T lymphocytes and immune resistance. by. In most mammals, aging is accompanied by thymus degeneration [12]. In the first year of human life, the number of thymocytes and hormone secretion levels reach a peak, and then decline several times until the age of 50 to 60, when the decline slows down [13].
The obvious manifestation of thymus degeneration is that starting from puberty, the thymus degenerates It causes a decrease in the production of initial T cells [14-15], an increase in memory T cells, and a loss of T cell receptor diversity [16-17]. This is accompanied by a decrease in T cell functional activity, which in turn causes immune decline [18-19]. At the same time, it is accompanied by defects in immune tolerance, causing autoimmune reactions [20].
T lymphocytes and aging
The occurrence of some physiological events in old age is related to the reduction in the number and function of acquired immune cells. T Decreased cell production and loss of TCR diversity are the result of thymic atrophy, including a decrease in thymic cortex and medulla and an increase in adipose tissue.
Certain profound changes in T cells in older adults underlie acquisition Most of the basis for hypoimmunity is the weakening of the body's defense capabilities. The consequences can lead to increased susceptibility to tumors, increased incidence of autoimmune diseases, increased susceptibility to infectious diseases, slower recovery, and reduced rejection of tissue transplants.
B lymphocytes and aging
Research in recent years has shown that B cells also change during aging, with the absolute number of B cells declining [24] and defects in antibody class conversion and recombination [25]. In addition, when aging, not only the quality and quantity of antibodies produced are different from those of young people, but autoantibodies also increase significantly. In addition to producing antibodies, B cells also have regulatory effector functions. Memory B cells and naive B cells can produce various cytokines and chemokines, especially memory B cells produce high levels of pro-inflammatory cytokines. Due to the increase in memory B cells in the elderly, it may be related to the increase in inflammatory aging (inflammaging) and chronic inflammatory diseases in the elderly [26].
As age increases, the immune effect of the elderly declines significantly. , the number of B cells mobilized under the same antigen intensity stimulation is only 1/10 to 1/50 of that in normal adulthood. For example, after vaccination with influenza vaccine, the seropositive protection rate for those aged 60 to 74 years is 41% to 58%, and the positive protection rate for those over 75 years old drops to 29% to 46%. Age-related changes in the cellular composition of the B cell family are a major contributor to poor antibody responses to vaccination and infection in the elderly [26].
Natural killer cells (NK) and aging
The innate immune response is non-specific and has no immune memory, and is the earliest response to pathogens. Innate immunity mainly includes monocytes/macrophages, NK cells, natural killer T cells (NKT), dendritic cells, neutrophils, etc., which change significantly with age [28].
Taking NK cells as an example, the number of NK cells in the elderly Increased, but decreased NK cell toxicity, as measured by levels of cytokine and chemokine production per cell, and unchanged antibody-dependent cytotoxicity. Aged NK cells have reduced killing toxicity and mature disorders. Studies have shown that changes in NK cell toxicity are related to zinc balance imbalance in the elderly. The function of NK cells can be significantly improved after zinc supplementation [30].
Age is related to T cell activity
Immune cells and prevention of aging
Early research shows that as we age, senescent T cells accumulate in the spleen, causing immune decline. Animal experiments have confirmed that compared with the control group, the survival time of young mice was shortened after receiving spleen cells from old mice. Another experiment showed that infusing autologous or allogeneic matched young T cells into splenectomy old mice can significantly extend the survival time [31]. Therefore, it is possible to store a person's immunoactive cells in adolescence at low temperature and then infuse them back into old age to repair declining immune function and prolong life.
Take NK cells as an example. NK cells are important in the body. The function of immune cells is to eliminate cancerous cells, senescent cells and abnormal cells in the body. NK cells are derived from hematopoietic stem cells and mature in the bone marrow. It accounts for about 10% to 15% of the total number of lymphocytes in the peripheral blood and about 3% to 4% in the spleen. It can also appear in the lungs, liver and intestinal mucosa, but is rare in the thymus, lymph nodes and thoracic duct.
The role of NK cells is to kill targets by releasing granzymes and activating death receptors cell. Studies have shown that perforin-mediated exocytosis is the main mechanism by which NK cells clear senescent cells [35]. NK cells bind to receptors on the surface of senescent cells, release perforin, granzymes and cytokines, induce the generation of apoptosis signals, promote senescent/diseased cells to undergo apoptosis, restore the balance of the microenvironment in the body, and reduce inflammation. At the same time, it stimulates and restores the production of new cells in the body, increases cell activity, improves cell quality, prevents and delays cell lesions, and restores the functions of cells, organs and immune systems, thereby achieving the goals of disease prevention, recovery and anti-aging.
Immune cell technology
Applications in aging and disease
Among aging-related diseases, with the rapid development of aging, the incidence of tumors in the elderly is increasing. The reasons are complex, among which innate immunity and acquired immunity The decline of the system is an important factor. The occurrence and development of tumors are the evolution process of a new organism in the limited space and time of the body. The genome of tumor cells interacts with the body's immune system in the microenvironment where tumors live, and they engage in a co-evolutionary game. Survive, develop or be restricted and eliminated.
The immune system is While defending against the invasion of foreign organisms, it is also responsible for maintaining the internal stability of the body and responding and processing abnormal or dysfunctional cells in a timely manner [37]. The results of in-depth research suggest that the immune system plays a double-edged sword role in the development of tumors. Unless immune The system eradicates dysfunctional tissues or cells in a timely manner. Chronic immune surveillance can lead to tumor immune sculpture, and the results can have two aspects: immune escape and invasion.
That is, tumor immune escape is caused by immune editing; tumor growth is promoted through incomplete inflammatory response. The two mechanisms interact to promote tumor development [38]. Therefore, it is very important to remove aging and diseased cells in time to prevent the further occurrence and development of tumors.
Adoptive T cell (ACT) technology is currently undergoing more clinical research. ACT mainly includes TIL, TCR, CAR, LAK, CIK, DC, NK cells and other major categories. It is the infusion of immune cells. Injected into patients in the hope of enhancing their anti-tumor capabilities. T cells can find tumors by "cruising" in the blood and settle there. In theory, T cells can be expanded in vitro to reach clinically required numbers, and can Provides longer-lasting anti-tumor effects.
Tumor-infiltrating lymphocytes (TIL)
TIL is the earliest ACT reinfusion cell. TIL is isolated from tumor cells, expanded with IL-2 in vitro, and then reintroduced into the system. infused into lymphodepleted patients with advanced melanoma. The results show that TIL can recognize intracellular tumor antigens through the interaction between MHC-I and T cell receptors (TCR). The clinical response rate of patients is 50% to 70%, and even 22% have seen complete tumor regression [39].
Tumor metastasis has almost disappeared
Dendritic cells (DC)
DC is the main component of the adaptive immune response, and T cell-mediated tumor immunity mainly relies on specific DCs Present tumor antigens, thereby activating killer T cells [40]. The key to generating efficient DCs is the selection of tumor antigens and optimized cell culture conditions, while using combined immunotherapy regimens to achieve the purpose of treating tumors [41]. DC cell therapy is not feasible for everyone. It prefers individual precision treatment and has significantly different effects on different types of patients [42].
Cytotoxic T cells (CTL)
DC cell-linked T cell therapy makes progress in virus-related tumors. CTL cells are isolated from peripheral blood, expanded in vitro/imposed with tumor specificity, and then infused back to the patient. There are tumor-derived peptides on the MHC-I of CTL, which can "lock" and activate the T cell receptor (TCR) that binds to it, allowing T cells to proliferate and produce anti-tumor properties. Currently, cytomegalovirus (CMV)-specific CTL have entered the exploratory stage of clinical trials for the treatment of glioblastoma [43].
Natural killer cells (NK)
NK cells express a variety of inhibitory receptors and activating receptors on their surface. In clinical practice, after allogeneic hematopoietic stem cell transplantation, donor NK cells are used to treat hematological tumors, increase hematopoietic stem cell implantation, reduce graft rejection, and enhance the anti-leukemia effect [44]. Selecting an appropriate NK cell donor can improve the effect of tumor treatment.
Cytokine-induced killer (CIK)
CIK is a T lymphocyte in human peripheral blood. CIK directly kills tumor cells by releasing perforin and granzyme. , or indirectly kill tumor cells by secreting a variety of cytokines. In addition, it can also induce tumor cell apoptosis by activating apoptosis genes. CIK therapy can be used to remove residual cancer cells, prevent recurrence and metastasis, and reduce the toxic side effects of radiotherapy and chemotherapy [45].
T cell receptor (TCR) technology
< p style="margin-bottom: 10px;">The mechanism of action of TCR is to introduce new genes into ordinary T cells, so that the new T cells can express TCR and be effective Recognize tumor cells and guide T cells to kill tumor cells. TCR technology is limited by the isolation of tumor-specific antigenic peptides. Retrovirally expressed αβTCR-T cells that recognize the melanoma MART1 antigen have shown clinical effects for the first time [46]. In addition, TCR technology has also achieved certain results in the treatment of liver cancer, breast cancer, ovarian cancer, etc. [47].
Chimeric Antigen Receptor (CAR) Technology
CAR is a chimeric antigen receptor on the surface of T cells. CAR recognizes tumor antigens with non-MHC restriction characteristics, and No antigen processing or presentation is required. However, only a few tumor-specific targets can be identified, and chimeric antibodies are potentially immunogenic [48]. CAR-T was first used in hematological malignancies. The most successful result so far is CAR-T that recognizes CD19. There are now 27 clinical trials studying CD19 CAR-T in the treatment of hematological tumors. However, in solid tumors, CAR-T has made limited progress. Most solid CARs have only transient antitumor activity [47].
Research on immunity and aging is still in the development stage. As the basis for studying cellular and molecular changes in aging, the system has received more and more attention from scholars. The application of immune cell technology to enhance immune function and delay the aging process and disease occurrence has gradually been recognized in domestic and foreign applications. In addition, in the treatment of aging-related diseases, such as the application of immune cell technology in malignant tumors, more and more attention has been paid, and major breakthroughs have been achieved.