CN117883478B - Application of non-classical T cells in preparation of medicines for treating spinal cord injury - Google Patents
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of CD3 +TCRαβ+CD4‑CD8‑NK1.1‑ non-classical T cells in preparation of a medicine for treating spinal cord injury. The spinal cord injury is a traumatic spinal cord injury. Experimental results show that the CD3 +TCRαβ+CD4‑CD8‑NK1.1‑ non-classical T cells can promote the recovery of exercise capacity after spinal cord injury and improve the spinal cord inflammation microenvironment. CD3 +TCRαβ+CD4‑CD8‑NK1.1‑ non-classical T cells are able to improve neurological function by modulating the immune microenvironment. The invention discovers the application of CD3 +TCRαβ+CD4‑CD8‑NK1.1‑ non-classical T cells in the aspect of treating spinal cord injury for the first time, and has important theoretical significance and clinical transformation value.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in preparation of a medicine for treating spinal cord injury.
Background
Spinal cord injury (Spinal Cord Injury, SCI) is a severe disabling disease, mostly caused by trauma. About 25-50 ten thousand people worldwide suffer from spinal cord injury caused by car accidents, violence, falling and the like each year. This severe disabling disease can lead to sensory and motor dysfunction below the lesion plane and thus to complications such as neuropathic pain, cramps, decubitus ulcers and bladder and bowel dysfunction, with a severe reduction in the quality of life of the patient.
To date, the treatment of spinal cord injury remains a fort of medical problems, becoming a "world ridge" that is difficult to surmount. The spinal cord injury process is complex, and the early stage is mainly caused by apoptosis and deletion of axons, oligodendrocytes and neurons; then the blood brain barrier is destroyed, and a large amount of inflammatory cell infiltration is induced; in the later stage, cavitation, glial scar and myelin sheath fall off at the damaged part to induce atrophy and apoptosis of distal nerve cells, block regeneration of axons and limit functional recovery. Surgical treatment, drug treatment, rehabilitation treatment and the like are the main schemes for clinically treating spinal cord injury at present, but can not effectively reverse the pathological degree of the damaged spinal cord, and influence functional recovery.
There are few treatments currently available for SCI. New techniques such as gene therapy and stem cell transplantation hold promise in treating SCI, but many technical challenges need to be addressed before these therapies can be used in clinical treatment. Therefore, the exploration of new therapeutic schemes for safely, effectively and conveniently treating spinal cord injury is still urgent, and the method has important theoretical significance and clinical conversion value.
The non-classical T cells are the T cells with the immunoregulation function discovered in recent years, compared with the classical CD 4T lymphocytes and CD 8T lymphocytes, the antigen recognition is strictly limited by MHCI and II molecules, the non-classical T cells are not strictly limited by MHCI and II molecules, are closer to the innate immune cells in the aspects of action time, recognition mode and the like, and have the characteristics of quick response and wide recognition. Neutrophils have been reported to promote polarization of CD3 +TCRαβ+CD4-CD8- non-classical T cells to Th1 and to mediate anti-tumor immunity by secreting interferon (Interferon-gamma, IFN-gamma). Our earlier studies showed that in situ transplantation of non-classical T lymphocyte subset cells CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells significantly reduced the expression of focal inflammatory factors and promoted restoration of neural function.
Heretofore, there has been no report on the treatment of spinal cord injury for non-classical T cells.
Disclosure of Invention
The invention aims to fill the blank of the prior art, solve the problems of insufficient medicaments or poor curative effects of medicaments for treating spinal cord injury clinically used at present, and provide the application of CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in preparing medicaments for treating spinal cord injury.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention provides an application of CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in preparing a medicament for treating spinal cord injury.
Alternatively, in the above use, the method for preparing the CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cell comprises the steps of: spleen and lymph node of 6-8 week old C57BL mice are ground by 200 μm screen and erythrocyte is lysed to obtain lymphocyte suspension. The mouse T cell enrichment column is used for enriching T cells in lymphocyte suspension, and CD 3 +TCRαβ +CD4 -CD8 -NK1.1- non-classical T cells are sorted by flow cytometry by using an anti-CD 8/CD19/NK1.1/Ter119/CD4/CD 25/TCRgamma delta antibody.
Alternatively, in the above use, the spinal cord injury is a traumatic spinal cord injury.
Alternatively, in the above use, the traumatic spinal cord injury is a spinal cord incomplete injury.
Alternatively, in the above use, the treatment of spinal cord injury is inhibition of inflammatory factor expression, and improvement of neurological function by modulation of immune microenvironment.
Alternatively, in the above use, the treatment of spinal cord injury is to promote recovery of motor ability after spinal cord injury.
Preferably, the exercise capacity recovery is manifested by an increase in exercise capacity, a shortening of the incubation period of the exercise and a significant increase in amplitude.
Alternatively, in the above use, the drug is a cell preparation comprising the CD3 +TCRαβ+CD4-CD8-NK1.1- non-canonical T cell population.
Alternatively, in the above use, the cell preparation further comprises a pharmaceutically acceptable carrier, diluent or excipient.
Alternatively, in the above use, the cell preparation is a liquid preparation.
Alternatively, in the above use, the cell preparation is for in situ injection.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides the application of CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in preparing medicaments for treating spinal cord injury for the first time. The spinal cord injury is a traumatic spinal cord injury. Experimental results show that CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells can promote the recovery of motor ability after spinal cord injury. CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells are able to improve neurological function by modulating the immune microenvironment. The invention discovers the application of CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in the aspect of treating spinal cord injury for the first time, and has important theoretical significance and clinical transformation value.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Fig. 1: motor function repair in spinal cord injured mice. Fig. 1A: different groups of mice assigned time point BMS scores; fig. 1B: 42 days after spinal cord injury, different groups of mice were BMS sub-scored; FIGS. 1C-1F: gait analysis related detection indexes: swing, standing, step length and step frequency of animals; fig. 1G: weight change at the designated time point for different groups of mice; fig. 1H: the BMS body weight of the mice in different groups changed 42 days after spinal cord injury.
Fig. 2: inflammatory factor change condition of spinal cord injury mice. Specifically, the expression of inflammatory factors IL-1α (FIG. 2A) and IL-6 (FIG. 2B) was varied in different groups of mice.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Examples
1. The experimental method comprises the following steps:
SPF-grade healthy female C57BL/6 (20.+ -.2 g) mice were purchased from Experimental animals technologies Inc. of Leriowa, beijing, randomly assigned to sham surgery groups, SCI groups and SCI+UTC (UTC refers to CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells in the examples, hereinafter UTC has the same meaning) intervention groups of 8 animals each. 2% isoflurane anesthetized mice, were fixed in prone position on an operating table, prepared for skin, conventionally sterilized, and were centrally placed in a posterior midline longitudinal incision with T10, revealing the T9-T11 spinous processes and lamina. Laminectomy was performed at a T10 level, and spinal cord percussions were performed with IH-400 impactor 70 KD force. The sham group underwent laminectomy only; SCI group received laminectomy and spinal cord injury modeling and injected with solvent control. Sci+utc transplant groups were subjected to laminectomy and spinal cord injury modeling, and immune cells UTC were injected. UTC injection, in the latter half hour of SCI model, cells were injected at four sites 0.8 x 10 5 UTC to the head/tail 2mm, left/right 0.3 mm, and depth 0.8 mm, respectively. The solvent control group was injected with the same volume of PBS at the same four sites.
The preparation method of the CD3 +TCRαβ+CD4-CD8-NK1.1- non-classical T cells comprises the following steps:
Spleen and lymph node of 6-8 week old C57BL mice are ground by 200 μm screen and erythrocyte is lysed to obtain lymphocyte suspension. The mouse T cell enrichment column is used for enriching T cells in lymphocyte suspension, and CD 3 +TCRαβ +CD4 -CD8 -NK1.1- non-classical T cells are sorted by flow cytometry by using an anti-CD 8/CD19/NK1.1/Ter119/CD4/CD 25/TCRgamma delta antibody.
BMS (Basso Mouse Scale) score: the hind limb movement function of the mice is evaluated by performing open field experiments at the appointed time point after injury, two trained observers independently perform the evaluation, and a single mouse is placed in a square open field with length multiplied by width (90 cm), and the behavior activity of the single mouse is continuously observed for 5min and recorded at the same time. The method is mainly used for evaluating the mobility of hind limb ankle joints, load walking and coordination of mice.
Results are expressed as mean and Standard Error (SEM). The data were analyzed by SPSS version 17.0 statistical software package. the t-test was used to determine significance between the two groups. One-way ANOVA tests were performed to compare three or more groups. P <0.05 considered the difference significant.
2. Experimental results:
2.1 UTC transplantation for promoting motor function repair of spinal cord injured mice
Immediately following spinal cord injury in mice, CD3 +TCRαβ+CD4-CD8-NK1.1- UTC was transplanted in situ, BMS scores and weight measurements were performed weekly after injury, BMS scores were observed to be higher in UTC cell transplantation groups than in SCI groups, significant differences were observed starting at 21 days post injury, and BMS scores were significantly increased for 28 days following injury, and for 42 days. While BMS sub-scores represent changes in animal fine behavior, study data indicate that the BMS sub-scores were significantly elevated in UTC cell-transplanted animals compared to SCI groups at 42 days post-injury. Furthermore, gait analysis data showed significant improvements in swing, stance and stride length for the UTC cell-transplanted animals compared to the SCI group. Meanwhile, the weight of the animal is observed to be obviously increased after UTC transplantation; especially at 35 and 42 days after injury, the body weight of the animals after UTC transplantation increased significantly compared to the SCI group. The results show that UTC in situ transplantation can significantly improve motor function recovery of mice after spinal cord injury. The specific experimental results are shown in fig. 1.
2.2 UTC transplantation inhibits inflammatory factor levels at the site of injury
Post-traumatic inflammation is a complex and critical progression that plays an important role in mediating secondary damage to SCI. Changes in cytokine expression suggest local and systemic inflammatory responses in both blood and spinal cord tissue.
The mice were transplanted with UTC immediately after spinal cord injury, and on the day after transplantation, changes in spinal cord tissue cytokines (IL-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, CCL2 (MCP-1), IFN- β, IFN- γ, TNF- α, and GM-CSF) were examined by flow cytometry, and study data showed significant downregulation of IL-1α and IL-6 after UTC injection. Results show that UTC transplantation can significantly improve the secretion of inflammatory factors at focal sites after spinal cord injury and improve local focal immune microenvironment. The specific experimental results are shown in fig. 2.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (8)
1. Use of CD3 +TCRαβ+CD4-CD8-NK1.1- non-canonical T cells in the preparation of a medicament for treating traumatic spinal cord injury.
2. Use according to claim 1, characterized in that: the traumatic spinal cord injury is an incomplete spinal cord injury.
3. Use according to claim 1, characterized in that: the treatment of traumatic spinal cord injury is to reduce inflammatory factor expression and improve neurological function by modulating immune microenvironment.
4. Use according to claim 1, characterized in that: the treatment of traumatic spinal cord injury is to promote the recovery of motor ability after spinal cord injury, which manifests as an increase in motor ability, a shortening of motor latency and a significant increase in amplitude.
5. Use according to claim 1, characterized in that: the drug is a cell preparation comprising the CD3 +TCRαβ+CD4-CD8-NK1.1- non-canonical T cell.
6. Use according to claim 5, characterized in that: the cell preparation further comprises a pharmaceutically acceptable carrier, diluent or excipient.
7. Use according to claim 6, characterized in that: the cell preparation is a liquid preparation.
8. Use according to claim 7, characterized in that: the cell preparation is for in situ injection.
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| CN117860782A (en) * | 2024-03-11 | 2024-04-12 | 中国康复科学所(中国残联残疾预防与控制研究中心) | Application of double negative T cells in preparation of medicines for treating spinal cord injury |
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| CN117860782A (en) * | 2024-03-11 | 2024-04-12 | 中国康复科学所(中国残联残疾预防与控制研究中心) | Application of double negative T cells in preparation of medicines for treating spinal cord injury |
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