CN109481666A - A kind of method for building up of blood of human body tumour PDX model - Google Patents
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Abstract
The invention discloses a kind of method for building up of blood of human body tumour PDX model, extract blood samples of patients tumour cell, and rabbit-anti human thymocyte immunoglobulin A TG and autologous patient serum is added, it is incubated for after mixing, after the completion of incubation, gained cell is resuspended, and is inoculated in Mice Body；The mouse of inoculation feeds cyclosporine CsA, since being inoculated with first 2 days blood tumor cell, continues 5-10 days.The present invention uses the novel high immunodeficiency type NCG mouse of China's independent research to establish human leukemia PDX model for the first time, the T cell in donor source is removed and inhibited by " human thymocyte immunoglobulin pre-processes sample and combines cyclosporine Long-term Oral ", ATG acts on the functional blockade of T lymphocyte the toxic effect joint CsA of lymphocyte, T lymphocyte immune function can persistently be inhibited, significantly improve the success rate of neoplastic hematologic disorder PDX modeling.
Description
Technical field
The present invention relates to neoplastic hematologic disorder experimental animal model construction method, specifically a kind of blood of human body tumour PDX model
Method for building up.
Background technique
According to recent statistics, disease incidence of the neoplastic hematologic disorder in China is about 3-4 people/100,000, in mortality of malignant tumors,
The 6th (male) and the 8th (women) is occupied, then occupies first in the adult of children and 35 years old or less.Specimens it is different
Kind of transplanting (PDX) model is a kind of preclinical study and medicine sieve animal model for malignant tumour creation.The model directly will
The fresh tumor tissues of patient are transplanted in immune-deficient mice body, and the tumor tissue cell library that can stablize passage is established,
Important support is provided for tumor-related plinth and clinical research.But there is also certain problems at this stage for this model.One
Aspect, PDX model construction are needed using immune-deficient mice.Although existing immune-deficient mice kind can expire
The demand of some kinds of solid tumor PDTX model foundation of foot, but leukaemia PDX model foundation still have larger difficulty and
Challenge, it is difficult to accomplish to stablize passage.In fact, will be unable to extensively if PDTX model cannot successfully reach the 3rd generation and the 4th generation
It is researched and developed applied to related disease research and clinical medicine.Foreign countries report application hyperimmunization defect NOG or NSG mouse of new generation into
The a variety of solid tumor PDX modelings of row, success rate is up to 70% or more, and the PDX of hematological system tumor modeling success rate is then lower than
30%.On the other hand, applicant and external part researcher observe, a small amount of patient source contained in leukaemia sample
T lymphocyte, meeting massive amplification in Mice Body in PDX modeling process, this problem, which is presently believed to be, causes blood swollen
The low another main cause of tumor PDX modeling efficiency.Previous researcher attempts to remove patient by " CD3 magnetic bead sorting " scheme
T lymphocyte in the monocyte of peripheral blood or derived from bone marrow.It but is not that whole T lymphocytes all expresses extracellular antigen
CD3, T cell precursor (including Pro-T, Pre-T) mainly express CD44, CD25 and c-kit, and the bis- positive T cells of CD4/CD8 are only
There is the CD3 of weakly positive to express.So " CD3 magnetic bead sorting method " cannot efficiently remove T lymphocyte, and higher cost, have one
Determine to obtain limitation, requires further improvement.
Competition of the field in intellectual property, therefore China disease animal model field all adds many-sided
Big research dynamics, accelerates research steps.Disease animal model modeling strategy is at this stage with gene modification class animal model
Main, idiopathic diseases animal model, environmental induction, physical factor induction etc. also relate to, continuous by researchers in recent years
Effort achieve certain achievement.For example, establishing Leukemia Model etc. in zebra fish using gene editing technology.
But compared to other entity tumors, leukaemia animal model species are limited, can not also provide enough quantity at this stage and be used for
Preclinical study hinders the prediction of clinical efficacy and the heterogeneous reaction of identification patient.Therefore, the white of efficient stable is established
Blood disease PDX model will generate huge economic benefit and social benefit.
Beginning PDX model foundation obtains a series of breakthroughs, the Mamoru of Japanese institute of lab animals within 2002
Ito study group, which cultivates, to be established with NOD/SCID as basis NOG (NOD/Shi-scid, IL-2R γ null) mouse model, he
By hybridization NOD/scid mouse and γ-, that chain IL-2 receptor knockout mice has been successfully established an immune function is seriously incomplete
Mouse species.2005, Jackson Lab, U.S. related researcher issued the NSG based on NOG again and has improved mould
Type.NOG and NSG mouse is compared with NOD/scid mouse, no T, the immune leakage of bone-marrow-derived lymphocyte, longer life expectancy, human body cell and group
It knits transplanting survival rate to be obviously improved, while nearly 70~80% normal or cancerous human's cell and tissue can be implanted into.But
It is many experiment mechanisms including China because of the independent intellectual property right without both types mouse, needs high price import
To carry out relevant experimental study, experimental cost is higher and obtains the time and quantity of mouse and can not be protected, unfavorable
In the foundation of extensive disease model.
Summary of the invention
The technical problem to be solved by the present invention is in view of the deficiencies of the prior art, provide, a kind of success rate is high, Neng Gouwen
Surely the method for building up of the blood of human body tumour PDX model passed on.
Clinically early stage before heteroplastic transplantation or after transplanting, urgency can be successfully reduced using the inhibitor for T lymphocyte
Property repel incidence and transplant relevant mortality.Clinic is through frequently with rabbit-anti human thymocyte immunoglobulin
(rabbit anti-human themocyte immunoglobulin, ATG) and cyclosporine (cyclosporin a, CsA) come
It treats graft versus host disease(GVH disease) (graft-versus-host disease, GVHD), this provides new think of for our research
Road.Rabbit Antithymocyte Globulin is antilymphocyte immunosuppressor, can be pressed down in the presence of complement (C1~C4)
The function of T (thymus gland dependence) lymphocyte processed.It can identify the active material on the T cell surface of thymic origin such as: CD2,
CD3, CD4, CD8, CD11a, CD25, HLA-DR and I grade of HLA, T cell is by complement-dependent lysis and by by monocyte
The Fc- dependence opsonin mechanism formed with phagocytosis is removed from circulation.Therefore, ATG be a kind of identification antigen compared with
Comprehensively, it can be directed to the T lymphocyte of thymic origin each stage of development, remove the strongest immunosuppressor of effect.Cyclosporine
It (CsA) is that a species specificity is higher, the strong immunosuppressor of inhibiting effect acts on to the property of can choose T lymphocyte activation
Initial stage, the normal hematopoiesis function without influencing marrow, the influence to B cell, granulocyte and macrophage are small.With to hematopoiesis group
Knit nontoxic, do not increase infection chance, it is easy to use the features such as, transplanting survival rate can be greatly improved.
Concrete scheme of the present invention is as follows:
A kind of method for building up of blood of human body tumour PDX model, includes the following steps:
(1) blood samples of patients tumour cell is extracted；
(2) it takes and rabbit Antithymocyte Globulin and autologous patient serum is added in step (1) blood tumor cell,
It is incubated for after mixing；
(3) after the completion of being incubated for, gained cell is resuspended, and is inoculated in Mice Body；
(4) mouse being inoculated with feeds cyclosporine, since being inoculated with first 2 days blood tumor cell, continues 5-10 days.
In step (1), extracting mode is acquisition blood samples of patients or marrow 5-50ml, carries out gradient using Ficoll separating liquid
Centrifugation；Isolated mononuclearcell uses brine, then with the resuspension of 0.5-2ml physiological saline.
In step (2), blood tumor cell is taken to be stored in physiological saline, is then added according to every mouse inoculation amount
50-400 μ g rabbit Antithymocyte Globulin and 1ml autologous patient serum.
Hypocomplementemia in the serum of leukaemia of part, requires supplementation with rabbit complement, and autoserum uses 1ml, requires supplementation with
Rabbit complement account for 20%-50%.
Preferably, the condition of the incubation are as follows: be incubated for 0.5-1.5h under 37 DEG C of constant temperature.
In step (3), inoculum concentration is gained mixed system after every mouse inoculation 0.1-0.25ml is resuspended, in mixed system
Blood tumor cell inoculum concentration is 2 × 105-1×106A, vaccination ways are through tail vein injection.
The mouse is female NCG mouse, and 6~8 week old are bought in model animal research institute, Nanjing University.
In step (4), the cyclosporine injected/and the amount of feeding is by 15-35mgkg-1·d-1Metering.
The utility model has the advantages that
1, the present invention establishes human leukemia using the novel high immunodeficiency type NCG mouse of China's independent research for the first time
PDX model.This kind of mouse (comes from existing and widely used NOG mouse (from Japanese Institute of Botany) and NSG mouse
Jackson Lab, the U.S.) compared to background it is purer, immune system defect is more serious, longer life expectancy, be suitble to long-term experiment observation and
Medication, heterograft high survival rate are the highest immunodeficient mouses of current tumor formation rate, particularly suitable for non-physical knurl, i.e. blood
The foundation of liquid system tumor.
2, for the monocyte of peripheral blood in patients or derived from bone marrow, the present invention uses " human thymocyte immunoglobulin
The T cell in donor source is removed and inhibited to pretreatment sample joint cyclosporine Long-term Oral ", and ATG makees the toxicity of lymphocyte
It is acted on functional blockade of the joint CsA to T lymphocyte, can persistently inhibit T lymphocyte immune function, significantly improve blood
The success rate of tumour PDX modeling.
Detailed description of the invention
The present invention is done with reference to the accompanying drawings and detailed description and is further illustrated, of the invention is above-mentioned
And/or otherwise advantage will become apparent.
Fig. 1 is B-ALL/NCG mouse model of the present invention.
Fig. 2 is P1 for B-ALL/NCG mouse peripheral blood and bone marrow smear.
Fig. 3 is that HE is dyed and immunohistochemistry shows the internal organs feelings such as source of people CD45 leukemiacell infiltration spleen, liver, kidney
Condition.
Fig. 4 is proliferation of 3 P2 of flow cytometer detection for mouse peripheral blood CD45/CD19 human leukemia cell in modeling process
Situation.
Fig. 5 is that P3 is observed for B-ALL NCG mouse drug sensitive experiment: saline control group, fludarabine joint and boron replace
Help rice+methotrexate (MTX) administration group tumor cell growth in vivo rate.
Specific embodiment
According to following embodiments, the present invention may be better understood.
One, Patient leukemic's sample preprocessing:
1, patient 5-50ml blood or 5-50ml marrow are acquired, carries out gradient centrifugation using Ficoll separating liquid, separation is suffered from
Person's mononuclearcell, after twice of mononuclearcell of brine, with the resuspension of 0.5-2ml mL normal saline, cytometer
Number.
2, ATG+ complement incubation group: clinical samples cell takes a part that ATG (200 μ g/ are only) and autologous patient serum is added
1ml (contains complement, if patient's own complement can not supplement a certain amount of rabbit complement completely) in serum, be incubated for 1 at 37 degree after mixing
Hour.Product leaves and takes the content that a part does flow cytometer detection identification T lymphocyte, while being resuspended after cell and counting, with every 1 ×
106A cell/0.2ml mixture/only, through tail vein injection Mice Inoculated.
Two, the raising of NCG mouse and inoculation:
1) mouse rearing conditions: female NCG mouse, 6-8 week old.Sub-cage rearing under the conditions of meeting SPF grades.Keep room temperature
18-25 DEG C, relative humidity 40%-60%, dedicated mouse cage, padding, feed and drinking-water are through 121 DEG C, 30min high pressure sterilization.Weekly
At least 1 time replacement padding.
2) NCG mice group: before being tested, taking 20 mouse to weigh, and record is divided into 2 groups at random, often
Group 10 is inoculated with according to above-mentioned cell processing mode respectively.
3) cyclosporine feeds processing: being not processed a group control group and is equipped with normal drinking water, ATG+ complement is incubated for Sets of Measurement and feeds
Take cyclosporine (CsA).
Three, it builds and is tied to form function judging quota:
1) overview index: after heterograft, whether there is or not listlessness, poor, thin, hunchbacked, abdomen of receiving for observation each group mouse
It rushes down, lose hair or feathers, the performance such as skin ulcer hemiplegia, blindness and whether there is or not tumor growths, periodically giving each group mouse weight, record data, see
60 days after examining to transplanting.
2) tail vein blood: mouse peripheral cells morphology and flow cytometer detection leukaemia immunophenotype are monitored weekly, is sentenced
Disconnected whether transplant is inoculated with successfully and whether T lymphocyte is in the intracorporal massive amplification of mouse.
3) selection transplanting is inoculated with successful mouse and puts to death: acquiring peripheral blood, marrow, spleen, the liver of mouse, is made into smear
Or printingout, the cellular morphology after Wright's staining is observed calculate tumour cell percentage；Spleen cell suspension is through flow cytometry
Analyze Immunophenotype analysis.
4) respectively tissue organopathy reason checks: PDX mouse is dissected at once after dying preceding or death, remaining mouse is in laminar-flow rack
Middle observation is unified to the 60th day after heterograft to put to death, and takes the tumor tissue and mouse liver, spleen, lung tissue, kidney, brain of mouse
Tissue, marrow, skin etc..Using conventional fixation, paraffin embedding, slice.Normal mouse NCG is taken to correspond to tissue for tissue disease
The control such as Neo-Confucianism.Taken tissue is dyed using Hematoxylin-eosin decoration method, to lotus knurl Histomorphological.Using
Immunohistochemical staining detects people's CD45 antigen presentation of PDX different tissues of mice.
5) leukaemia cell's vaccinization is passed on: extracting blood from primary plant NCG mouse living, or primary small using freezing
Mouse spleen suspension quickly thaws, brine, by every 1 × 106Cell is added in 0.2ml physiological saline and suspends again, passes through
Tail vein injection is inoculated with next generation NCG mouse.
Four, experimental result:
1, " ATG+CsA " scheme processing NCG mouse side reaction is small
In order to which the science of preliminary identification " ATG+CsA " theoretical foundation and the medication combined immune poison pair of two kinds of assessment are made
With we first attempt to be used for using ATG+ complement (200 μ g/, tail vein injection) joint CsA (35mg/kg, drinking-water are fed)
NCG mouse experiment (totally 6), continuous observation 2 months, mouse diet was drunk water without influence, and hair color and mobility are normal, do not make
The adverse reactions such as blood dysfunction and infection.
2, " ATG+CsA " scheme constructs B-ALL/NCG mouse model success
Fig. 1 is B-ALL/NCG mouse model: there is fur color dimness in mouse after 8-9 weeks after injecting blood tumour cell,
It is apathetic, movable phenomena such as reducing.There is the serious enlargement of spleen in dissection discovery mouse (shown in Fig. 1 black arrow).
Inventor has further separated an example recurrence refractory B cell acute lymphatic leukaemia B-ALL peripheral blood in patients source
Leukaemia cell, establishing P1 for B-ALL/NCG mouse, mouse peripheral blood and spleen cell has massive tumor cellular infiltration.
Fig. 2 is that P1 is observed for B-ALL/NCG mouse peripheral blood and bone marrow smear: visible a large amount of leukaemia cells.
But when expanding the P2 of number for mouse for the spleen suspension inoculation of mouse with P1, only some P2 is for mouse
(3 in 6) have leukaemia cell's amplification, in addition 3 mouse peripheral bloods and spleen occur a large amount of source of people T cells without
Leukaemia cell cannot stablize passage.After P1 is added 7 °C of incubation 1h of complement component 3 for mouse spleen suspension and ATG by us, connect again
P2 is for mouse 6 for kind, while feeding CsA, and whole mouse peripheral bloods flow cytometer detection occur in one month time as the result is shown
A large amount of leukaemia cells, and the phenomenon that T lymphocyte expands is not found.Source of people CD45 is shown using HE dyeing and immunohistochemistry
The internal organs situation such as leukemiacell infiltration spleen, liver, kidney, is shown in Fig. 3；In the full scope of spleen, the vein blood vessel of liver
There is a large amount of tumor cell invasion in area, the glomerulus region of kidney, and hematoxylin eosin stain and human antibody CD45 are presented
Dark positive expression.
3 P2 of flow cytometer detection were being modeled for the people B-ALL leukaemia cell for expressing CD45/CD19 in mouse peripheral blood
Proliferative conditions in journey.Respectively in modeling 10 days, 20 days, progress tail passages through which vital energy circulates blood sampling in 30 days and flow cytometer detection source of people CD45/CD19
Positive cell is shown in Fig. 4.It was found that has there is tumor cell proliferation in peripheral blood after modeling 10 days, as number of days increases ratio gradually
Increase, the ratio of 30 days 50% or more Shi Kezhan mouse peripheral bloods, this result shows that tumour cell in the B-ALL mouse model
The screening that passage, massive amplification, and proportion are applicable to later period drug can be stablized.
It is equally effective for mouse that such scheme is applied to 18 P3, and P3 can be successfully applied to subsequent medicine for mouse
In quick experiment.Fig. 5 is that P3 is observed for B-ALL/NCG mouse routine drug sensitive experiment: being and expands to certain amount using stablizing to build
P3 for B-ALL mouse carry out drug sensitive experiment, be divided into saline control group, bortezomib+methotrexate (MTX) administering drug combinations group,
Tumor cell growth in vivo rate is detected respectively, and bortezomib+methotrexate (MTX) administering drug combinations group is compared with control group as the result is shown, in early period
The tumour cell of the patient can be inhibited can not when medication with a large amount of proliferation of advanced stage tumours cell to a certain extent
Continue the proliferation degree of control tumour cell, prompts also to need further to explore the refractory B cell acute lymphatic leukaemia B- of the recurrence
The effective application method of ALL patient and other treatment modes.These results suggest that ATG adds the scheme needle of complement joint cyclosporine
It is effective to this example B-ALL mouse modeling.To sum up, acute lymphatic leukaemia is successfully constructed using the program, it is chronic
Lymphatic leukemia, a variety of hematological system PDX mouse models of chronic myelocytic leukemia CML, myeloma MM etc., and can be steady
Fixed passage, and can be successfully applied in later period drug sensitive test.
The present invention provides the thinking and method of a kind of method for building up of blood of human body tumour PDX model, specific implementation should
There are many method and approach of technical solution, the above is only a preferred embodiment of the present invention, it is noted that for this technology
For the those of ordinary skill in field, various improvements and modifications may be made without departing from the principle of the present invention, this
A little improvements and modifications also should be regarded as protection scope of the present invention.Existing skill can be used in each component part being not known in the present embodiment
Art is realized.
Claims (8)
1. a kind of method for building up of blood of human body tumour PDX model, which comprises the steps of:
(1) blood samples of patients tumour cell is extracted；
(2) it takes and rabbit Antithymocyte Globulin and autologous patient serum is added in step (1) blood tumor cell, mixing
After be incubated for；
(3) after the completion of being incubated for, gained cell is resuspended, and is inoculated in Mice Body；
(4) mouse being inoculated with feeds cyclosporine, since being inoculated with first 2 days blood tumor cell, continues 5-10 days.
2. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (1),
Extracting mode is acquisition blood samples of patients or marrow 5-50ml, carries out gradient centrifugation using Ficoll separating liquid；The single core of separation
Cell uses brine, then with the resuspension of 0.5-2ml physiological saline.
3. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (2),
Blood tumor cell is taken to be stored in physiological saline, it is thin that 50-400 μ g rabbit-anti people's thymus gland then is added according to every mouse inoculation amount
Born of the same parents' immunoglobulin and 1ml autologous patient serum.
4. the method for building up of blood of human body tumour PDX model according to claim 3, which is characterized in that the patient is certainly
Need to fill into the rabbit complement of 20-50vt% in body serum.
5. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (2),
The condition of the incubation are as follows: be incubated for 0.5-1.5h under 37 DEG C of constant temperature.
6. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (3),
Inoculum concentration is gained mixed system after every mouse inoculation 0.1-0.25ml is resuspended, blood tumor cell inoculum concentration in mixed system
It is 2 × 105-1×106It is a.
7. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (3),
The mouse is female NCG mouse, and 6~8 week old are bought in model animal research institute, Nanjing University.
8. the method for building up of blood of human body tumour PDX model according to claim 1, which is characterized in that in step (4),
The amount of feeding of the cyclosporine is by 15-35mgkg-1·d-1Metering.
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