荷瘤小鼠脾脏功能紊乱型CD8~+T细胞数量的分析研究

目的分析荷瘤小鼠与正常小鼠脾脏功能紊乱型CD8~+T细胞(Tim-3~+/PD-1~+ CD8~+T细胞)的数量比例,预测肿瘤患者功能紊乱型CD8~+T细胞的情况,为改善肿瘤的免疫治疗提供参考。方法设置荷瘤小鼠组与正常小鼠组,每组各3只,分别从两组小鼠脾脏中提取分离获得CD8~+T细胞,用FITC标记的PD-1抗体、PE标记的Tim-3抗体与CD8~+T细胞共孵育,孵育后经流式细胞术检测获得数据,并分析结果。结果正常小鼠组脾脏CD8~+T细胞占脾脏T淋巴细胞总数百分比为7.7%,荷瘤小鼠组脾脏CD8~+T细胞占脾脏T淋巴细胞总数百分比为1.2%,两组的CD8~+T细胞数量有明显差异性(χ~2=0.299,P=0.02);正常小鼠组脾脏功能紊乱型CD8~+T细胞占CD8~+T细胞总数的百分比为1.17%,荷瘤小鼠组脾脏功能紊乱型CD8~+T细胞占CD8~+T细胞总数的百分比为1.17%,两组数据差异无统计学意义(χ~2=0.00,P=1.00)。结论荷瘤小鼠与正常小鼠脾脏组织中功能紊乱型CD8~+T细胞的数目无明显差异。     

白细胞介素-2联合环磷酰胺对乳腺癌荷瘤小鼠调节性T细胞的影响

目的：调节性T细胞（Regulatory T cells,Treg）被认为能够抑制抗肿瘤免疫反应,从而促进肿瘤生长。环磷酰胺（Cyclophosphamide,CTX）是个常规化疗药物,现在更多的注意力集中在其小剂量应用时可以删除Treg。了解小剂量环磷酰胺联合白细胞介素-2（Interleukin-2,IL-2）对4T1Balb/c乳腺癌荷瘤小鼠调节性T细胞的影响及其抗肿瘤效果。方法：通过皮下接种4T1乳腺癌细胞建立乳腺癌Balb/c荷瘤小鼠模型;20只荷瘤小鼠随机分为IL-2＋NS组、PBS＋CTX组、IL-2＋CTX组及PBS＋NS组,在种瘤第10天开始对荷瘤小鼠分别经腹腔按方案给药。在种瘤后第16天人道处死小鼠,采用流式细胞术检测小鼠脾脏中CD4＋CD25＋调节性T细胞数量,应用ELISA法检测血清干扰素-γ浓度,电子称称量肿瘤重量。结果：与对照组相比,在应用IL-2后,荷瘤小鼠脾脏CD4＋CD25＋/CD4＋比值增加,在应用IL-2的同时使用小剂量CTX可减少CD4＋CD25＋/CD4＋的比值;单次及联合用药均可提高血清INF-γ浓度;联合用药可减少肿瘤重量。结论：小剂量CTX可以减少由使用IL-2所增加的Treg数量,促进抗肿瘤免疫,提高IL-2的抗瘤效果,从而抑制肿瘤生长。该研究可能为乳腺癌的临床治疗提供一种有效的方法。     

Hepal-6 RNA脉冲BMDCs瘤苗抗小鼠HCC免疫效应的研究

目的观察Hepal-6RNA脉冲BMDCs瘤苗能否激发有效的机体抗肿瘤免疫反应。方法用Hepal-6RNA脉冲骨髓分离培养5d的BMDCs,瘤苗的抗肿瘤效应通过C57BL/6J小鼠肝细胞癌(HCC)模型验证,即C57BL/6J小鼠皮下接种Hepal-6细胞8d后,成瘤小鼠分为2组:对照组(注射无血清RPMI-1640)和实验组(足垫部注射Hepal-6RNA脉冲BMDCs瘤苗),30d后处死小鼠并取淋巴结、脾和瘤体冰冻切片,进行CD4、CD8、CD25和Foxp3免疫组织化学染色。结果免疫组织化学检测显示,淋巴结、脾、肿瘤内有大量CD4+T细胞、CD8+T细胞、CD25+T细胞和Foxp3+Tregs细胞浸润。与对照组小鼠比较,足垫部注射Hepal-6RNA脉冲BMDCs瘤苗的实验组小鼠淋巴结、脾、瘤内CD4+T细胞和CD8+T细胞浸润显著增加,CD25+T细胞和Foxp3+Tregs浸润明显减少。结论 Hepal-6RNA脉冲BMDCs瘤苗能下调小鼠HCC瘤内CD25+T细胞和Foxp3+Tregs浸润,促进CD4+T细胞和CD8+T细胞的增殖和活化,增强D4+T细胞、CD8+T细胞归巢至淋巴结和脾,具有抗瘤免疫效应。     

肝癌小鼠外周血及脾脏T淋巴细胞亚群的变化及其意义

目的:观察小鼠原位肝癌模型外周血以及脾脏T淋巴细胞亚群与正常小鼠之间的差异变化,探讨其差异变化的意义。方法:在正常KM小鼠肝脏种植H22细胞,建立小鼠原位模型。采用流式细胞术,以健康正常小鼠为对照,检测肝癌小鼠外周血以及脾脏T淋巴细胞亚群的变化。结果:与健康正常小鼠相比,肝癌小鼠外周血CD4~+T淋巴细胞、CD4~+/CD8~+比例有显著性降低,CD8~+T淋巴细胞显著性升高;脾脏CD3~+、CD4~+T淋巴细胞有显著性降低。结论:小鼠原位肝癌模型外周血以及脾脏T淋巴细胞亚群发生异常,免疫系统紊乱,可以反映小鼠肝癌的发生、发展。     

蛋氨酸脑啡肽单独或联合IL-2、IFN-γ对小鼠CD4+T细胞作用的研究

通过体内外MENK单独或联合IL-2、IFN-γ对C57BL/6小鼠CD4+T细胞数量,CD4+T细胞mRNA表达量以及细胞因子产生量的变化,来阐明MENK对CD4+T细胞的免疫效应.应用流式细胞术、酶联免疫吸附试验、RT-PCR方法检测C57 BL/6小鼠体内外单独应用MENK,或联合IL-2、IFN-γ后,CD4+T细胞数量,CD4+T细胞mRNA的表达量及上清中细胞因子含量.MENK单独或联合IL-2、IFN-γ,在体内能显著增加小鼠CD4+T细胞数量,CD4+T细胞mRNA表达量及细胞因子IL-2、IFN-γ含量;体外MENK单独应用可以显著增加小鼠CD4+T细胞数量,CD4+T细胞mRNA表达量及细胞因子IL-2、IFN-γ含量;而体外MENK联合IL-2或IFN-γ与MENK单独作用时相比无明显差异.MENK单独或联合IL-2、IFN-γ,在体内能上调CD4+T细胞的免疫效应.     

黄芪多糖对免疫抑制模型小鼠Treg细胞及Th17细胞亚群的影响

本研究旨在探讨黄芪多糖对免疫抑制模型小鼠CD4+CD25+调节性T细胞(Treg细胞)和CD4+Th17细胞亚群功能的影响。通过小鼠腹腔注射环磷酰胺建立免疫抑制动物模型,应用黄芪多糖对免疫抑制小鼠进行治疗,采用流式细胞仪分析脾脏中CD4+T细胞、CD4+CD25+Treg细胞的比例,ELISA检测血清IL-17的水平。结果表明:与模型对照组比较,黄芪多糖高、中剂量明显降低小鼠脾脏CD4+T细胞数的比例(P0.05),同时黄芪多糖上调小鼠脾脏CD4+CD25+Treg细胞数的比例(P0.05),降低免疫抑制小鼠血清IL-17的水平,尤其1.0 g/(kg·d)剂量组的IL-17水平下降较为明显(P0.01)。提示黄芪多糖具有提高免疫抑制小鼠CD4+CD25+Treg细胞数的比例、降低CD4+T细胞的数量及抑制IL-17分泌活性的作用。     

石见穿多糖对H22荷瘤小鼠的抗肿瘤免疫调节作用

前期研究发现石见穿多糖(polysaccharides from Salvia chinensis Benth.,PSSC)能有效抑制H22肝癌细胞在昆明小鼠体内的生长。在此基础上,本研究进一步探讨了PSSC对H22荷瘤小鼠免疫器官和免疫细胞的影响。通过在昆明小鼠右腋皮下注射H22肝癌细胞构建荷瘤小鼠模型。采用流式细胞术、免疫组织化学染色、酶联免疫法等实验方法评价PSSC对CD4+T细胞、CD8+T细胞、自然杀伤细胞(NK细胞)抗肿瘤免疫能力的影响。结果表明PSSC可以有效增加小鼠的脾脏/胸腺指数并促进Con A/LPS刺激的脾细胞增殖。同时,PSSC剂量依赖性地增加了荷瘤小鼠外周血单核细胞、脾脏及淋巴结中CD8+T细胞比例并提高CD8+T细胞与NK细胞在肿瘤组织中的组分含量。注射PSSC后,CD4+T细胞分泌免疫促进因子IFN-γ和IL-2的量增加,而分泌免疫抑制因子IL-4和IL-10的量减少。这一系列实验研究结果表明PSSC具有显著的抗肿瘤免疫增强活性。     

SLE带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+FoxP3~+调节性T细胞的表达及相关性研究

目的:检测系统性红斑狼疮(systemic lupus erythematosus,SLE)合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞的表达及相关性,探讨其在SLE合并带状疱疹发病中的临床意义。方法:采用流式细胞术检测30例SLE患者、30例SLE合并带状疱疹患者及30例健康对照者外周血中CD4~+/CD8~+T淋巴细胞亚群表面CD28的表达及CD4~+CD25~+Fox P3~+Treg细胞的表达水平,并分析SLE合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞表达的相关性。结果:SLE合并带状疱疹组患者急性期外周血CD4~+T淋巴细胞比率、绝对计数显著降低,CD4~+、CD8~+T淋巴细胞表面的CD28表达下调,CD4~+CD25~+Fox P3~+Treg细胞水平显著高于SLE组及健康对照组,SLE合并带状疱疹组患者外周血CD4~+CD25~+Fox P3~+Treg水平与CD4~+CD28~+水平成负相关(P均0.05)。结论:SLE合并带状疱疹患者CD4~+、CD8~+T细胞活化异常,CD4~+CD25~+Fox P3~+Treg细胞可能参与抑制了T细胞的活化。     

砂生槐多糖提取物对免疫抑制模型小鼠Treg和Th17的影响

为了开发藏药砂生槐的药用价值,本文拟研究其多糖提取物对免疫抑制小鼠调节性T细胞(Treg)和Th17的影响。水提醇沉法提取砂生槐枝条多糖物质,腹腔注射环磷酰胺建立免疫抑制小鼠模型,模型小鼠经砂生槐多糖灌胃干预后,分离脾细胞,流式细胞术检测CD4+T细胞比例和CD4+CD25+Treg细胞比例;收集血清,ELISA检测IL-17水平。结果显示,各剂量组砂生槐多糖均能够引起免疫抑制小鼠的脾脏CD4+CD25+Treg细胞比例明显增多(P0.05),同时明显抑制IL-17的产生(P0.05)。以上结果提示砂生槐多糖可能通过上调Treg而抑制免疫功能,同时抑制IL-17的产生,发挥免疫抑制作用。     

人工合成胸腺肽α1对正常小鼠和免疫抑制荷瘤小鼠的免疫调节作用

目的:本研究通过对正常小鼠和免疫抑制荷瘤小鼠皮下注射人工合成胸腺肽α1 (sTα1).方法:检测各组小鼠淋巴细胞亚群比率、T淋巴细胞增殖数量和脾细胞细胞因子的表达水平三个指标,来判定sTα1对小鼠免疫功能的影响.结果:sTα1可提高小鼠外周血CD4+T细胞比率、降低CD8+T细胞比率,使CD4+/CD8+的T细胞比率增加.sTα1能明显加强正常小鼠、环丙酰胺(CTX)免疫抑制小鼠和荷瘤+CTX免疫抑制小鼠的脾淋巴细胞的增殖(P＜0.5),明显促进正常小鼠及各免疫抑制组小鼠脾细胞细胞因子mIL-2和mIFNγ释放(P＜0.5).结论:sTα1可促进T细胞的快速成熟,活化T细胞,纠正了荷瘤和化疗药物产生的免疫抑制作用,有效刺激免疫系统,促进Th1型细胞免疫反应.     

Early expression of stem cell-associated genes within the CD8 compartment after treatment with a tumor vaccine

Using a mouse neuroblastoma cell line, we have demonstrated that vaccination of tumor-free mice with a cell-based vaccine leads to productive immunity and resistance to tumor challenge, while vaccination of tumor-bearing mice does not. The T cell immunity induced by this vaccine, as measured by in vitro assays, is amplified by the depletion of Treg. Our goal is to understand this barrier to the development of protective cellular immunity. mRNA microarray analyses of CD8⁺ T cells from naïve or tumor-bearing mice undergoing vaccination were carried out with or without administering anti-CD25 antibody. Gene-expression pathway analysis revealed the presence of CD8⁺ T cells expressing stem cell-associated genes early after induction of productive anti-tumor immunity in tumor-free mice, prior to any phenotypic changes, but not in tumor-bearing mice. These data demonstrate that early after the induction of productive immune response, cells within the CD8⁺ T cell compartment adopt a stem cell-related genetic phenotype that correlates with increased anti-tumor function.     

CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review

CD8⁺ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 ⁺ T cell-mediated antitumor immune responses. Thus, CD8 ⁺ T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 ⁺ T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 ⁺ T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated–inflamed [I–I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 ⁺ T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)–ligand (PD-L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 ⁺ T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.     

Effects of CD4+ and CD8+ T cells in tumor-bearing mice on antibody production

The function of T cell subsets in tumor-bearing mice was examined using an in vitro culture system of anti-(sheep red blood cell) antibody production, which is known to be dependent on T cells. The helper function of T cells of fibrosarcoma-MethA-bearing mice in antibody production decreased with the tumor stage of the mice. T cells were separated into CD4⁺ and CD8⁺ cells for further analysis of T cell subsets by the panning method using monoclonal antibodies. The helper function of CD4⁺ T cells in antibody production began to decrease significantly in tumor-bearing mice 1 week after the tumor transplantation. On the other hand, the suppressive function of CD8⁺ T cells was retained and had not decreased in the mice even 3 weeks after the transplantation. The same changes in function of CD4⁺ and CD8⁺ T cells were also observed in Methl-bearing mice. These results suggested that this tumor-associated immunosuppression in antibody production is attributable to the decrease in helper activity of CD4⁺ T cells and the maintenance of the suppressive activity of CD8⁺ T cells.     

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8⁺ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8⁺ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8⁺ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8⁺ T cells, which led to higher ratios of CD8⁺/Treg and CD8⁺/CD11b⁺Gr-1⁺ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8⁺ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells.     

Local injections of OK432 can help the infiltration of adoptively transferred CD8+ T cells into the tumor sites and synergistically induce the local production of Th1-type cytokines and CXC3 chemokines

The effect of local injections with streptococcal preparation OK432 on the antitumor effect induced by adoptive immunotherapy (AIT) was investigated. Draining lymph node cells on day 14 after B7-P815 inoculation were used for AIT after in vitro stimulation. AIT on days 7 and 10 showed no effect on the growth of s.c. established P815 mastocytoma, but local injections with OK432 into the tumor sites on days 3, 6 and 9 resulted in a moderate antitumor effect. On the other hand, the combination therapy significantly suppressed tumor growth, and the tumor-bearing mice survived longer than those receiving only one of the treatment modalities. The significant infiltration of CD4⁺ or CD8⁺ T cells and multiple necrosis in the tumor sites were observed only when the tumor-bearing mice were treated with the combination therapy. In addition, a transfer experiment using labeled effector cells revealed these infiltrated CD8⁺ T cells and CD4⁺ T cells to be derived from the donor and the host respectively. More importantly, the combination therapy clearly led to higher expression of the mRNA for Th1-type cytokines and CXC3 chemokines in the tumor sites than resulted from each of the treatment modalities alone. Collectively, these results indicate that local injections with OK432 can help the infiltration of adoptively transferred CD8⁺ T cells into the tumor sites and synergistically induce the local production of the Th1-type cytokines and CXC3 chemokines. Received: 3 April 2000 / Accepted: 5 May 2000     

Adjuvant IL-15 does not enhance the efficacy of tumor cell lysate-pulsed dendritic cell vaccines for active immunotherapy of T cell lymphoma

There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to stimulate CD8⁺ T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent tumor-specific CD8⁺ T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8⁺ T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8⁺ CD44^hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15 following vaccination did not secrete increased levels of tumor-specific TNF-α or IFN-γ or have enhanced C6VL-specific CTL activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing vaccinated mice. Thus, while activated- and memory-phenotype CD8⁺ T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8⁺ T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8⁺ T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively transferred transgenic CD8⁺ T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and activity of preexisting tumor-specific CD8⁺ T cells.     

Neem Leaf Glycoprotein Activates CD8+ T Cells to Promote Therapeutic Anti-Tumor Immunity Inhibiting the Growth of Mouse Sarcoma

In spite of sufficient data on Neem Leaf Glycoprotein (NLGP) as a prophylactic vaccine, little knowledge currently exists to support the use of NLGP as a therapeutic vaccine. Treatment of mice bearing established sarcomas with NLGP (25 µg/mice/week subcutaneously for 4 weeks) resulted in tumor regression or dormancy (Tumor free/Regressor, 13/24 (NLGP), 4/24 (PBS)). Evaluation of CD8⁺ T cell status in blood, spleen, TDLN, VDLN and tumor revealed increase in cellular number. Elevated expression of CD69, CD44 and Ki67 on CD8⁺ T cells revealed their state of activation and proliferation by NLGP. Depletion of CD8⁺ T cells in mice at the time of NLGP treatment resulted in partial termination of tumor regression. An expansion of CXCR3⁺ and CCR5⁺ T cells was observed in the TDLN and tumor, along with their corresponding ligands. NLGP treatment enhances type 1 polarized T-bet expressing T cells with downregulation of GATA3. Treg cell population was almost unchanged. However, T∶Treg ratios significantly increased with NLGP. Enhanced secretion/expression of IFNγ was noted after NLGP therapy. In vitro culture of T cells with IL-2 and sarcoma antigen resulted in significant enhancement in cytotoxic efficacy. Consistently higher expression of CD107a was also observed in CD8⁺ T cells from tumors. Reinoculation of sarcoma cells in tumor regressed NLGP-treated mice maintained tumor free status in majority. This is correlated with the increment of CD44^hiCD62L^hi central memory T cells. Collectively, these findings support a paradigm in which NLGP dynamically orchestrates the activation, expansion, and recruitment of CD8⁺ T cells into established tumors to operate significant tumor cell lysis.     

Reciprocal effects of Th1 and Treg cell inducing pathogen-associated immunomodulatory molecules on anti-tumor immunity

We have addressed the hypothesis that pathogen-associated immunomodulatory molecules may influence anti-tumor immunity through their pro- and anti-inflammatory activities and abilities to induce effector and regulatory T (Treg) cells. We found that CpG oligonucleotides (CpG) and cholera toxin (CT), which promote Th1 or Th2/Treg cell biased responses, respectively, had differential effects on tumor growth. Therapeutic peritumoral administration of CpG significantly reduced subcutaneous tumor growth and prolonged survival, whereas CT enhanced tumor growth and reduced survival. Peritumoral administration of CpG enhanced the frequency of IFN-γ-secreting and reduced IL-10-secreting CD4⁺ and CD8⁺ T cells, in the tumor and in the draining lymph nodes, whereas, CT significantly enhanced the frequency of CD4⁺CD25⁺Foxp3⁺ Treg cells, but reduced IFN-γ-secreting T cells infiltrating the tumor. In contrast to the beneficial effect of CpG in mice with subcutaneous tumors, CpG or CT had no protective effect against tumor growth in the lungs when given therapeutically by the nasal route. However, prophylactic intranasal administration of CpG significantly reduced the number of lung metastases and this was associated with an enhanced frequency of IFN-γ-secreting CD8⁺ T cells in the draining lymph node and enhanced tumor-specific CTL responses. Our findings demonstrate that pathogen-associated molecules can either inhibit or enhance anti-tumor immunity by selectively promoting the induction of effector or regulatory T cells, and that the environment of the growing tumor influences the protective effect. Joanne Lysaght and Andrew G. Jarnicki contributed equally.     

Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice

During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4⁺CD8⁺ immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.