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WT1 Pulsed Tib Neeg CD141+ Dendritic Cell Vaccine Muaj Peev Xwm Muaj Peev Xwm Zoo hauv Cov Tumor-Targeted Immunotherapy

Feb 20, 2024

Abstract:

Dendritic cells (DC) yog cov hlwb muaj zog uas ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv qog nqaij hlav, thiab lawv siv hauv kev tiv thaiv kab mob qog noj ntshav tau qhib lub peev xwm zais zais raws li kev kho mob zoo. Txhawm rau ua kom muaj peev xwm ua tiav ntawm DC, peb tau tsim cov tshuaj tiv thaiv DC lub npe hu ua CellgramDC-WT1 (CDW). CDW tau pulsed nrog WT1, ib qho antigen feem ntau qhia hauv cov qog nqaij hlav, thiab ntxias nrog zoledronate los pab DC maturation. Txawm hais tias peb txoj kev tshawb fawb yav dhau los tau tsom mus rau kev siv Rg3 ua tus inducer ntawm DC maturation, teeb meem nrog kev tswj kom zoo thiab kev nkag tau ua rau peb xaiv zoledronate ua lwm txoj hauv kev zoo dua. Tsis tas li ntawd, CDW secreted IL-12 thiab IFN-, uas ua rau muaj kev sib txawv ntawm cov kab mob tsis zoo T hlwb rau cov CD8+ T cells thiab elicited cytotoxic T lymphocyte (CTL) teb tawm tsam cov qog nqaij hlav cancer nrog WT1 antigens. Los ntawm kev lees paub tus kheej thiab kev ua haujlwm ntawm CDW, peb ntseeg tias CDW yog ib qho tshuaj tiv thaiv DC zoo dua qub thiab tuav cov peev xwm muaj txiaj ntsig hauv kev kho mob qog noj ntshav.

Desert ginseng-Improve immunity (2)

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Ntsiab lus:

DC tshuaj tiv thaiv; CD141; dendritic hlwb; zoledronate; T-cell activation; mob cancer immunotherapy; nqaij hlav; mob qog noj ntshav antigens; Wilms' qog1 (WT1); qog-associated antigens

1. Taw qhia

Mob qog noj ntshav yog qhov ua rau tuag thoob ntiaj teb, thiab thaum cov kev kho mob ib txwm muaj xws li kev phais, kws khomob, thiab irradiation, lawv feem ntau ua rau muaj kev phiv tsis zoo vim tsis muaj peev xwm sib txawv ntawm cov qog nqaij hlav cancer thiab ib txwm muaj [1]. Txawm li cas los xij, kev nce qib tsis ntev los no hauv kev tiv thaiv kab mob tau tso cai rau kev txhim kho cov tshuaj tiv thaiv kab mob qog noj ntshav, uas lub hom phiaj ua kom lub cev tiv thaiv kab mob rau cov qog nqaij hlav tshwj xeeb thiab ua rau txo qis cov kev mob tshwm sim [2]. Cov tshuaj tiv thaiv kabmob kheesxaws feem ntau yog siv cov qog nqaij hlav los yog cov qog tshwj xeeb antigens los ua kom cov antigen tshwj xeeb lymphocytes ntawm lub cev tiv thaiv kab mob [3]. Ua kom cov lymphocytes, feem ntau T hlwb, xav tias muaj txiaj ntsig zoo xws li cytotoxicity thiab cytokine ntau lawm los tswj kev mob qog noj ntshav [4]. Cov tshuaj tiv thaiv kab mob qog noj ntshav sib txawv siv cov txheej txheem tiv thaiv kab mob, xws li cov tshuaj tua kab mob ntuj (NK) hlwb [5] thiab cov hlwb dendritic (DC) [6]. Ntawm cov no, DC yog cov tshuaj tiv thaiv kab mob (APC) thiab ua lub luag haujlwm tseem ceeb hauv kev ua kom lub cev tiv thaiv kab mob los ntawm T hlwb. Cov yam ntxwv tseem ceeb ntawm DC muaj peev xwm ntes cov antigens thiab ua cov protein rau hauv peptide kom nthuav tawm rau T hlwb los ntawm cov loj histocompatibility complex (MHC) molecules. Txawm li cas los xij, DC suav nrog cov pej xeem sib txawv nrog txhua qhov chaw uas muaj cov phenotypes thiab cov haujlwm [7].

Desert ginseng-Improve immunity (15)

cistanche cog-nce kev tiv thaiv kab mob

DCs tau muab faib ntau rau hauv classical / pa DC (cDC), plasmacytoid DC (pDC), thiab monocyte-derived DC (mo-DC). Muaj ob pawg loj ntawm cDC: hom 1 DC (cDC1), uas feem ntau nthuav tawm cov tshuaj tiv thaiv uas siv MHC chav kawm I kom tshem tawm CTL cov lus teb los ntawm CD8+ T cell (CTL), thiab hom 2 DC (cDC2), uas siv MHC chav II los txhawb cov lus teb los ntawm CD4+ T cell (tus pab T cell) [8]. Plasmacytoid DCs yog ib qho tshwj xeeb ntawm DC uas tau tshwj xeeb hauv kev zais zais hom I interferon (IFN) [9]. Mo-DC feem ntau koom nrog kev mob thiab txhawb TH17 lub cev tiv thaiv kab mob [10] (Daim duab 1A). Tam sim no, mo-DC feem ntau siv nyob rau hauv kev tshawb fawb DC anti-cancer immunotherapy [11–13]. Txawm hais tias mo-DC tau txais txiaj ntsig zoo thiab muaj kev nyab xeeb, kev kho mob qis tau cuam tshuam nws txoj kev siv dav. Qhov kev txwv ntawm mo-DC yog pom nyob rau hauv vitro, qhov uas lawv qhia ib tug txwv tsis pub muaj peev xwm tsiv mus nyob rau cov qog nqaij hlav los ua kom muaj zog cytotoxic T lymphocyte (CTL) cov lus teb [14]. Txhawm rau kov yeej cov kev txwv ntawm cov hom tshuaj tiv thaiv DC tam sim no, cDC1 tau raug xaiv hauv txoj kev tshawb no, vim nws muaj peev xwm nthuav tawm cov tshuaj tiv thaiv antigen zoo tshaj plaws thiab ua kom pom cov lus teb siab CTL. Txawm hais tias kev tshawb fawb ntawm cov tshuaj tiv thaiv cDC1 tau nce siab, cDC1 tseem tsis tau tshawb nrhiav hauv kev sim tshuaj [15].

image

Peb tau txais cov hlwb mononuclear (MNC) los ntawm cov pob txha pob txha thiab tom qab ntawd cais CD34+ hlwb (hematopoietic qia hlwb) siv MACS® Cell Separation txheej txheem. Cells tau proliferated siv granulocyte-macrophage colony-stimulating factor (GM-CSF), qia cell factor (SCF), thiab Fms-zoo li tyrosine kinase receptor 3 (FLT3)-ligand, uas ncaj qha induces sib txawv rau hauv DC [16], thiab sib txawv. rau hauv DC yog induced nrog GM-CSF thiab interleukin 4 (IL{10}}). Tsis paub qab hau DC lees paub WT1 protein raws li cov antigen thiab yog matured siv zoledronate. WT1 (Wilms 'tumor1) antigen yog heev qhia nyob rau hauv ntau yam malignancies thiab ntau yam ntawm cov qog nqaij hlav. Yog li, WT1 tau siv los ua ib lub hom phiaj ntawm kev tiv thaiv kab mob qog noj ntshav [17]. Zoledronate yog ib hom tshuaj ntawm chav kawm bisphosphonate, uas yog dav siv rau kev kho mob ntawm ob leeg pob txha thiab pob txha metastasis. Tsis tas li ntawd, zoledronate inhibits enzyme farnesyl diphosphate synthase, uas ua lub luag haujlwm hauv txoj hauv kev mevalonate thiab tom qab prenylation ntawm me me GTPase proteins, xws li Ras [18]. DC matured yog ces ua tiav raws li DC tshuaj tiv thaiv (Daim duab 1A). Feem ntau, DC matured secrete ntau yam cytokines rau induce lub activation ntawm lub cev tiv thaiv kab mob [19] thiab khi ncaj qha rau T hlwb rau antigen nthuav qhia [20]. T hlwb reacted nrog DC los ua pab T hlwb (CD4+) los pab lub cev tiv thaiv kab mob los yog cytotoxic T hlwb (CD8+) ncaj qha pib los tiv thaiv mob qog noj ntshav [21] (Daim duab 1B). Qhov muaj pes tsawg leeg ntawm cov tshuaj tiv thaiv DC tau lees paub los ntawm kev ntws cytometry, thiab kev ua haujlwm ntawm cov tshuaj tiv thaiv tau txheeb xyuas los ntawm cytokine secretion test, T cell hloov, thiab cytotoxic T Lymphocyte (CTL) assay.

Desert ginseng-Improve immunity (23)

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Nyem qhov no mus saib Cistanche Enhance Immunity khoom

【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692

2. Cov txiaj ntsig

2.1. Flow Cytometry Profiles Illustrating DC Vaccine with High CD141+ Qhia

Txhawm rau paub meej tias tus kheej ntawm DC, ntau cov cim tau raug tshuaj xyuas, suav nrog CD141 (qhov siv ntau tshaj cDC1 tus cim), CD1c (tus cim ntawm cDC2), thiab CD303a (ib qho cim ntawm pDC). Tsis tas li ntawd, HLA-DR, CD80, thiab CD86, uas yog cov cim ua kom muaj zog, kuj tau txheeb xyuas. Nyob rau hauv sib piv rau 70% ntawm cDC2 pom nyob rau hauv tib neeg DC ntawm cov ntshav, DC uas tau tsim feem ntau muaj cDC1 (CD{11}} hlwb), thiab ob qhov zoo tshwm sim ntawm CD141+CD1c+ nyob rau hauv activated DC yog kuj lees paub [22,23]. Tsis tas li ntawd, cov txiaj ntsig tau pom muaj kev ua haujlwm siab heev rau DC (Daim duab 2A, B). Cell morphology hloov pauv kuj tau taug qab siv cov ntshav suav (CBC) rau lub sijhawm sib txawv hauv DC ntau lawm. Thaum feem ntau ntawm cov hlwb proliferate li monocytes nyob rau hauv lub proliferation theem (Table 1), qhov sib txawv theem ua rau ib tug maj mam txo nyob rau hauv monocytes mus rau ib theem ntawm ploj mus rau qhov kawg ntawm cov txheej txheem ntau lawm.

Figure 2. Identification of CDW subsets. Phenotypic characteristics of DC. During the differentiation process, the DC were pulsed with WT1 protein and treated with 1 µM zoledronate for 3 h. The data show the expression of stimulatory marker and subtype of DC representative of human DC (n = 5) (A). Results are shown as dot plots (B).

Daim duab 2. Kev txheeb xyuas ntawm CDW subsets. Phenotypic yam ntxwv ntawm DC. Thaum lub sij hawm sib txawv, DC tau hloov nrog WT1 protein thiab kho nrog 1 µM zoledronate rau 3 h. Cov ntaub ntawv qhia tau hais tias tus cwj pwm stimulatory thiab subtype ntawm DC tus neeg sawv cev ntawm tib neeg DC (n=5) (A). Cov txiaj ntsig tau pom zoo li dot plots (B).

Table 1. Thaum lub sij hawm tus txheej txheem ntawm proliferation thiab sib txawv ntawm CD34+ hlwb mus rau DC, phenotypic pauv tau soj ntsuam siv CBC.

Table 1. During the process of proliferation and differentiation from CD34+ cells to DC, phenotypic changes were analyzed using CBC.

2.2. Plasmatic theem ntawm IL-12 thiab IFN- Cytokines txiav txim los ntawm ELISA

Ntawm ntau cytokines secreted los ntawm DC, feem ntau tus neeg sawv cev yog IL-12 thiab IFN- . IL-12 tswj kev mob los ntawm kev sib txuas hauv lub cev thiab hloov lub cev tiv thaiv kab mob. Feem ntau ntawm IL-12-cov teebmeem tshwm sim yog kho los ntawm kev tso tawm ntawm IFN- thiab tau dhau los ua qhov tseem ceeb rau kev cuam tshuam ntawm Th1 hlwb. IFN- ua lub luag haujlwm tseem ceeb hauv kev ua kom lub cev tiv thaiv kab mob ntawm tes thiab, tom qab ntawd, stimulation ntawm antitumor tiv thaiv kab mob [24-26]. Txhawm rau txhawm rau txheeb xyuas qhov ua tau zoo ntawm CDW, IL-12, thiab IFN- secretion theem tau txheeb xyuas los ntawm kev cuam tshuam nrog T hlwb. Thaum T cell-tsuas yog thiab T cell kho nrog unpulsed DC tej yam kev mob ua rau cov qib secretion uas zoo sib xws, thaum cov pab pawg tau muab piv nrog cov T cell + CDW pawg, CDW induction ntawm T hlwb yielded ob zaug ntawm IL. -12(Daim duab 3A) thiab nce qib ntawm IFN- (Daim duab 3B).


Figure 3. Induction comparison of CDW on T cells via cytokine analysis. The secretion of IL-12 (A) and IFN-γ (B) was measured in T cell only (activated IL-2 and Trans ACT), T cell + unpulsed DC and T cell + CDW co-culture supernatant using ELISA assay (n = 3). ELISA was performed using the supernatant at the time of completion. Analysis was performed through SigmaPlot. *** p < 0.001.

Daim duab 3. Induction piv ntawm CDW ntawm T hlwb ntawm cytokine tsom xam. Kev tso tawm ntawm IL-12 (A) thiab IFN- (B) tau ntsuas hauv T cell nkaus xwb (activated IL-2 thiab Trans ACT), T cell + unpulsed DC thiab T cell + CDW co-culture supernatant siv ELISA assay (n=3). ELISA tau ua tiav siv lub supernatant thaum lub sijhawm ua tiav. Kev tshuaj xyuas tau ua los ntawm SigmaPlot. *** p < 0.001.

2.3. Zoledronate's Effect on the Differentiation and Maturation of cDC1 in CDW

Nyob rau hauv txoj kev tshawb no dhau los, Rg3 [27], ib qho ginsenoside pom nyob rau hauv Panax ginseng, tau siv los ntxias cov maturation ntawm DC; Txawm li cas los xij, cov khoom kawg muaj ib txheej ntawm impurities, ua rau muaj teeb meem hauv kev tswj kom zoo. Zoledronate tau siv los hloov Rg3 kom kov yeej qhov teeb meem no, thiab nws cov txiaj ntsig ntawm qhov induction ntawm DC maturation raug tshuaj xyuas. Qhov sib txawv tseem ceeb tshaj plaws ntawm qhov cuam tshuam ntawm ob yam khoom yog lub peev xwm ntawm zoledronate kom tawm tau qhov kev qhia tshwj xeeb ntawm cDC1 (CD141+ cell) nto marker (Daim duab 4A). Yog li, raws li cDC1 paub tias yog qhov zoo tshaj DC subtype hauv kev nthuav qhia antigen, zoledronate tau raug xaiv rau qhov induction ntawm DC maturation [18]. Lub sijhawm kho kom zoo ntawm zoledronate hauv inducing DC maturation kuj tau soj ntsuam. Txawm hais tias 24 teev kev kho mob tau txais txiaj ntsig txaus ntawm CD141+ hlwb, CD141+ cell feem hauv qhov txiaj ntsig kev kho mob 3 h tau ntau dua li ntawm kwv yees li 20%, thiab CD86 (co- stimulatory marker) feem ntau hauv 3 h kev kho mob kuj tseem ntau dua 30%. Tsis tas li ntawd, ua tib zoo xav txog cov txheej txheem ntawm kev txiav txim ntawm zoledronate, lub sijhawm kho luv luv ntawm 3 h piv rau 24 h tau pom tias muaj txiaj ntsig zoo hauv kev ua kom zoo dua ntawm DC (Table 2).

Figure 4. Effect of zoledronate on the differentiation and maturation of cDC1 in DC vaccine production. Effects of zoledronate in DC vaccine. In the process of DC vaccine production, 3 hr treatment with zoledronate induces differentiation and maturation of DC to cDC1 and yields a higher level of CD141 marker. Phenotype markers were analyzed by flow cytometry to compare Rg3 (n = 4) and zoledronate (n = 5), which were used for the induction of DC maturation. *** p < 0.001.

Daim duab 4. Cov nyhuv ntawm zoledronate ntawm qhov sib txawv thiab kev loj hlob ntawm cDC1 hauv DC cov tshuaj tiv thaiv. Cov teebmeem ntawm zoledronate hauv DC tshuaj tiv thaiv. Hauv cov txheej txheem ntawm DC cov tshuaj tiv thaiv, 3 hr kho nrog zoledronate induces sib txawv thiab maturation ntawm DC rau cDC1 thiab yields ntau dua ntawm CD141 marker. Phenotype markers tau soj ntsuam los ntawm kev khiav cytometry los sib piv Rg3 (n=4) thiab zoledronate (n=5), uas tau siv rau induction ntawm DC maturation. *** p < 0.001.

Table 2. Cov nyhuv ntawm lub sij hawm kho zoledronate (3 h thiab 24 h) ntawm cov cim saum npoo.

Table 2. Effect of zoledronate treatment times (3 h and 24 h) on surface markers.

2.4. CDW Vaccination-Induced WT1 Antigen-Specific T Cell Responses

Figure 5. CDW increases CD8+ T cells to promote cytotoxicity against cancer cells. Effect of CDW on T cell response assessed via CTL. IL-2 and Trans-Act are T cell stimulators and were used to stimulate T cells. The activated T cells were co-cultured with DC for the first induction, which lasts for seven days, and the second induction which extends to 10 days. The changes in the T cell subtype were analyzed via flow cytometry (A). The T cells cultured for 10–14 days were co-cultured with cancer cells expressing WT1 according to appropriate ratios in a 96-well plate. Post-72 h, the survival rate of cancer cells was analyzed using CCK8 (B–D). T cells induced by CDW group (B). T cell only group (activated IL-2 and Trans ACT) (C). T cells induced by unpulsed DC group (D). * p < 0.05, *** p < 0.001.

Daim duab 5. CDW nce CD8+ T hlwb los txhawb cytotoxicity tawm tsam cov qog nqaij hlav cancer. Cov txiaj ntsig ntawm CDW ntawm T cell teb ntsuas ntawm CTL. IL-2 thiab Trans-Act yog T cell stimulators thiab tau siv los txhawb T hlwb. Cov activated T hlwb tau co-cultured nrog DC rau thawj induction, uas kav rau xya hnub, thiab lub thib ob induction uas txuas mus rau 10 hnub. Cov kev hloov hauv T cell subtype tau txheeb xyuas los ntawm flow cytometry (A). Cov kab mob T hlwb tau coj los rau 10-14 hnub tau koom ua ke nrog cov kab mob qog noj ntshav uas qhia WT1 raws li qhov sib piv tsim nyog hauv 96- lub phaj zoo. Tom qab -72 h, qhov ciaj sia taus ntawm cov qog nqaij hlav cancer tau txheeb xyuas siv CCK8 (B–D). T cells induced los ntawm CDW pawg (B). T cell nkaus xwb pab pawg (activated IL-2 thiab Trans ACT) (C). T hlwb induced los ntawm unpulsed DC pawg (D). * p < 0.05, *** p < 0.001.

2.5. Kev lees paub ntawm Kev Nyab Xeeb ntawm CellgramDC Tshuaj Tiv Thaiv

Hauv ob pawg tswj hwm (3.4 × 104 hlwb / tsiaj txhu lossis 1.7 × 105 hlwb / tsiaj txhu), tsis muaj qhov txawv txav tau pom zoo txog kev tuag lossis cov tsos mob dav dav vim yog cov tshuaj siv tshuaj.

Thaum lub sijhawm soj ntsuam, tsis muaj kev hloov pauv tseem ceeb hauv toxicologically hauv pawg tswj hwm (3.4 × 104 hlwb / tsiaj txhu lossis 1.7 × 105 hlwb / tsiaj txhu) vim yog cov tshuaj siv tshuaj. Cov kev soj ntsuam suav nrog lub cev hnyav (Daim duab 6A), urinalysis (Daim duab 6B), kev noj zaub mov noj, tshuaj xyuas ophthalmological, kuaj hematological, kuaj ntshav biochemical, qhov hnyav ntawm lub cev, kev txiav txim siab, thiab kev kuaj mob hauv zos (Ntxiv 1, Tables S1-S9). Ntau yam kev ntsuam xyuas tau lees paub los ntawm kev sib piv stem-derived DC (CellgramDC) thiab monocyte-derived DC (mo-DC). Kev ciaj sia thiab qog loj ntawm cov nas kuj tau sim. Cov qog loj hauv pawg-DC tau txo qis ntau dua 50% piv rau cov pab pawg mo-DC, thiab tus nqi ciaj sia kuj tau nce ntxiv, lees paub qhov muaj zog tiv thaiv kab mob (Ntxiv 2).

Figure 6. Subcutaneous dose toxicity study of CellgramDC in C57BL/6 mice. To test the safety and toxic response of the CellgramDC, female and male mice of the C57BL/6 strain were subcutaneously injected with CellgramDC for a total of six weeks (one injection per week). The safety of Cell gramDC was tested by subcutaneous injection into female and male mice for a total of six weeks (one injection per week). Administration groups consisted of two groups: 10 mice injected with 3.4 × 104 cells/animal and 15 mice injected with 1.7 × 105 cells/animal. A negative control group was comprised of 15 mice and was injected intravenously with a solution composed of excipient, plasma solution-A/human serum albumin (HSA) 90% + DMSO 10%, and saline for six weeks (one injection per week). In order to test for a reversible toxic response, five mice from each comparison group, negative control group, and 1.7 × 105 cells/animal administration group were given two weeks of the recovery period. During the recovery period, weight check (A), urinalysis (B), general symptoms, feed intake measurement, and ophthalmological examination were observed. Following the observation period, hematological tests, blood biochemical tests, and organ weight measurements were performed, as well as visual and histopathological examinations at necropsy.

Daim duab 6. Subcutaneous koob tshuaj toxicity kawm ntawm CellgramDC hauv C57BL/6 nas. Txhawm rau kuaj kev nyab xeeb thiab tshuaj lom ntawm CellgramDC, poj niam thiab txiv neej nas ntawm C57BL / 6 hom tau txhaj tshuaj subcutaneously nrog CellgramDC rau tag nrho rau lub lis piam (ib txhaj tshuaj ib lub lis piam). Kev nyab xeeb ntawm Cell gramDC tau kuaj los ntawm kev txhaj tshuaj subcutaneous rau poj niam thiab txiv neej nas rau tag nrho rau lub lis piam (ib qho tshuaj ib lub lis piam). Cov pab pawg tswj hwm muaj ob pawg: 10 nas txhaj nrog 3.4 × 104 hlwb / tsiaj txhu thiab 15 nas txhaj nrog 1.7 × 105 hlwb / tsiaj txhu. Ib pawg tswj tsis zoo yog suav nrog 15 nas thiab tau txhaj tshuaj intravenously nrog cov tshuaj uas muaj cov tshuaj ntxiv, cov tshuaj plasma-A / human serum albumin (HSA) 90% + DMSO 10%, thiab saline rau rau lub lis piam (ib txhaj tshuaj ib lub lis piam). Txhawm rau kuaj xyuas cov lus teb rov qab tau tshuaj lom, tsib nas los ntawm txhua pawg sib piv, pawg tswj tsis zoo, thiab 1.7 × 105 hlwb / pawg tswj hwm tsiaj tau muab ob lub lis piam ntawm lub sijhawm rov qab los. Thaum lub sijhawm rov qab los, kuaj qhov hnyav (A), urinalysis (B), cov tsos mob dav dav, ntsuas kev noj zaub mov, thiab kuaj pom qhov muag pom. Tom qab lub sijhawm soj ntsuam, kuaj hematological, kuaj ntshav biochemical, thiab ntsuas qhov hnyav ntawm lub cev, nrog rau kev kuaj pom thiab histopathological ntawm necropsy.

Peb tau lees paub qhov ruaj khov thiab ua tau zoo ntawm CellgramDC. CDW uas yog pulsed nrog WT1 thiab kho nrog zoledronate kuj yuav raug kuaj rau toxicity thiab kev ua tau zoo thiab cov txiaj ntsig tau zoo tuaj.

3. Kev sib tham

Hauv cov tshuaj tiv thaiv CDW uas tau tsim tawm, cDC1 yog qhov siab tshaj plaws hauv kev faib ua feem thiab pom tias muaj kev ua haujlwm siab. Lub cDC1 yog cov hlwb uas muaj peev xwm tshaj tawm antigen zoo tshaj plaws thiab muaj lub luag haujlwm rau lub luag haujlwm tseem ceeb ntawm DC. Xav seb yuav ua li cas cDC1 ua ib qho tsis tshua muaj DC [~0.03% ntawm PBMC] [28], qhov tseem ceeb ntawm CD141+ cov pej xeem hauv CDW yog qhov txiaj ntsig zoo hauv kev ua kom muaj txiaj ntsig ntawm cov tshuaj tiv thaiv. Tsis tas li ntawd, cDC1 hauv CDW zais cytokines (IL-12 thiab IFN- ) nyob rau theem siab thiab muaj peev xwm ua kom muaj kev sib txawv ntawm cov hlwb tsis zoo rau CD8+ T cells. Hauv peb txoj kev tshawb fawb yav dhau los, Rg3 tau siv los ua qhov kev loj hlob, tab sis muab qhov nyuaj rau kev tau txais cov khoom siv thiab kev tswj xyuas zoo ntawm cov khoom kawg, zoledronate tau siv los ua ib qho kev hloov pauv los daws cov teeb meem no. DC induced los ntawm zoledronate tau kawm los txheeb xyuas nws lub luag haujlwm ua tus inducer ntawm V 9 δ T cell activation [29]. Zoledronate yog ib chav kawm ntawm bisphosphonates, thiab bisphosphonates induce cov kev ua ntawm δ T hlwb kom sai thiab abundantly tsim proinflammatory cytokines [30], coj qhov no rau hauv kev txiav txim siab, peb tsim peb qhov kev sim los kuaj cov teebmeem ntawm kev kho mob luv luv. Hauv peb txoj kev tshawb fawb, zoledronate (piv rau Rg3) induced activation ntawm CD8+ T hlwb hauv CDW thiab kuj nce qib cDC1. Thawj qhov kev sim tshuaj tau ua rau DC induced los ntawm Rg3 (NCT 046158-45) los ntawm peb txoj kev tshawb fawb dhau los, tab sis cov txiaj ntsig tsis tau tshaj tawm. Txawm li cas los xij, peb cia siab tias yuav txhim kho cov txiaj ntsig hauv kev sim tshuaj ntsuam xyuas yav tom ntej siv DC induced los ntawm zoledronate muab cov kev tshawb pom tam sim no.

Cistanche deserticola-improve immunity (6)

cistanche cog-nce kev tiv thaiv kab mob

Tsis ntev los no, muaj ntau txoj kev tshawb fawb nyob ib puag ncig tiv thaiv kab mob qog noj ntshav, thiab cov kev tshawb fawb tshaj plaws yog CAR-T [31,32] thiab CAR-NK [33,34]. Cov kev kho mob no tau lees paub lawv cov kev ua tau zoo thiab muaj kev cia siab heev rau kev kho mob qog noj ntshav. Txawm li cas los xij, CAR-T tsuas yog siv rau kev kho mob qog noj ntshav, uas suav nrog ib feem me me ntawm txhua hom mob qog noj ntshav [35]. Tsis tas li ntawd, cov neeg mob tuaj yeem raug kev txom nyem los ntawm kev kho mob, xws li cytokine release syndrome (CRS) [36]. Txhawm rau kov yeej cov kev tsis txaus no, kev siv tshuaj tiv thaiv kab mob siv NK hlwb raug tshawb fawb. NK hlwb yog cov lymphocytes muaj zog heev thiab lub hom phiaj mob qog noj ntshav los ntawm ntau qhov kev qhia dav dav ua kom ligands. Yog li ntawd, NK hlwb tuaj yeem hais txog cov kev txwv ntawm autologous CAR T cell therapy. Txawm li cas los xij, muaj ntau qhov tsis zoo rau kev siv NK hlwb, xws li kev nyuaj hauv cell kab lis kev cai, tam sim no hauv kev ua haujlwm siab tshaj plaws ntawm cellular kinetics, thiab luv luv intrinsic longevity nrog rau kev nco phenotype nyob rau hauv lub neej ncua thiab teb [34,37 , 38] ib. Lwm qhov kev tshawb fawb suav nrog kev sib xyaw ua ke siv DC lossis T hlwb thiab cov tshuaj tiv thaiv kab mob tiv thaiv kab mob xws li anti-PD1 (programmed cell death protein1) [39] lossis anti-PD-L1 (programmed death-ligand1) [40]. Kev sib koom ua ke ntawm cov tshuaj no tso cai rau lub hom phiaj ntawm kev tiv thaiv kab mob qog noj ntshav microenvironment thiab kev tshawb fawb ntxiv yog nyob rau hauv kev ua kom cov kev ua tau zoo ntawm cov kev kho mob no.

Cistanche deserticola-improve immunity (7)

Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob

Kev tshawb fawb txog kev tsim cov tshuaj tiv thaiv DC rau kev tiv thaiv kab mob tsis tu ncua, thiab ntau qhov kev nce qib tau ua hauv daim teb no. DC ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob siab tshaj plaws, thiab DC tshuaj tiv thaiv tuaj yeem muab qhov zoo dua piv rau lwm hom kev tiv thaiv kab mob qog noj ntshav. Vim tias DC tsis tua cov qog nqaij hlav ncaj qha, cov hlwb ib txwm tsis muaj kev cuam tshuam, tshem tawm cov kev mob tshwm sim. Tsis tas li ntawd, los ntawm kev sib tw DC nrog WT1, ib qho antigen feem ntau qhia hauv ntau cov qog nqaij hlav [17], DC tshuaj tiv thaiv tuaj yeem tsom cov qauv qog nqaij hlav. Ua ntej txiav txim siab ntawm WT1 protein antigen, peb tau sim nrog ntau hom antigens. Los ntawm kev siv cov khoom lag luam zoo, nrog rau ntau yam antigens xws li peptide, captivator, lossis pop mix, antigen nrog cov nyhuv loj tshaj yog thaum siv los ua cov protein. Yog li ntawd, peb siv WT1 protein rau antigen pulsing. Txoj kev kawm dav tshaj plaws hauv DC txoj kev kho mob siv mo-DC pulsed nrog WT1 nrog rau kev kho mob [12]. Kev nyab xeeb thiab kev tiv thaiv kab mob ntawm mo-DC tau lees paub los ntawm kev sim tshuaj [13]. Thaum lwm qhov kev tshawb fawb tshuaj tiv thaiv DC tsim nws cov tshuaj tiv thaiv siv monocyte-derived DC los ntawm cov ntshav, peb kwv yees tias DC tau los ntawm cov qia hlwb yuav muaj peev xwm nce ntxiv. Tsis tas li ntawd, nws tau paub tias cDC muaj lub zog ntau dua li mo-DC, txhawb nqa peb mus rau qhov kev tshawb fawb no. Yog li ntawd, CDW tej zaum yuav yog ib qho kev xaiv zoo dua rau mo-DC, vim nws cov ntsiab lus tseem ceeb yog cDC1, DC subtype uas muaj peev xwm ua tau zoo tshaj plaws. Txawm hais tias cov kev ua cytotoxic zoo ib yam hauv T hlwb + unpulsed DC pawg thiab CDW pawg, peb xav tias qhov no yog vim tsis muaj zog DC kuj yog hom cDC1 cell. Txawm li cas los xij, CDW tuaj yeem ua kom muaj zog tiv thaiv qog noj ntshav los ntawm kev ua kom cov neeg nyob hauv cDC1. Los ntawm txoj kev tshawb fawb preclinical, peb tau sim rov ua cov tshuaj toxicity ntawm DC tshuaj tiv thaiv. Txoj kev txhim kho thiab tsim cov txheej txheem ntawm CDW tau raug txheeb xyuas, thiab peb cia siab tias yuav ua cov kev tshawb fawb ntxiv los ntsuas cov txiaj ntsig zoo ntawm CDW. Thaum qhov kev ua tau zoo tau lees paub hauv vitro, kev tshawb fawb tshuaj toxicity tau ua rau kev siv tau zoo hauv vivo. Thaum cov txiaj ntsig ntawm kev sim tshuaj siv CDW tau tshaj tawm, peb npaj siab los coj peb cov kev tshawb fawb hauv cov kev taw qhia uas yuav txhim kho kev tshawb fawb tam sim no.

Cov ntaub ntawv

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