病毒治愈的荷瘤鼠对再次植入S180细胞的实验研究

给病毒治愈的Ｓ１８０荷瘤小鼠腹腔内植入不同剂量的Ｓ１８０细胞和Ｅｈｒｌｉｃｈ细胞,随着Ｓ１８０细胞的植入量的增加,其存活率从９－％下降至１５％,与植入的Ｓ１８０细胞量成反比。而用ＥｈｒＬｉｃｈ腹水瘤细胞入病毒治愈的Ｓ１８０小鼠,５０００／只和１００００／只两组各存活１０％,其它组１００％死亡。     

甲型流感病毒免疫治疗S_（37）腹水瘤的实验研究

用甲型流感病毒７５－３９株鼠肺适应型,免疫治疗Ｓ３７腹水瘤小鼠,存活率达９３．３％。体外流感病毒感染Ｓ３７肿瘤细胞,经不同时间观测,到３天时Ｓ３７细胞经胎盘蓝染色发现细胞１００％死亡。而对照组Ｓ３７细胞死亡率为１０％左右（ｐ＜０．０１）。进一步研究病毒免疫治疗Ｓ３７腹水瘤小鼠的机理,发现经病毒感染后小鼠ＮＫ细胞杀伤活性升高达５８％,正常鼠ＮＫ活性为２２％,两者有显著性差异（ｐ＜０．０１）。另外,检测病毒注射后小鼠腹腔巨噬细胞的吞噬活性也随之升高。     

蛇毒心脏毒素对荷瘤小鼠的抗肿瘤作用初步研究

目的探讨蛇毒心脏毒素（ＣＴＸ）对荷瘤小鼠Ｓ１８０腹水瘤细胞生长抑制的影响。方法小鼠腹腔接种Ｓ１８０活瘤细胞,连续１０ｄ分别腹腔注射ＣＴＸ０．８ｍｇ／ｋｇ、０．４ｍｇ／ｋｇ、０．２ｍｇ／ｋｇ,分析统计荷瘤小鼠的体重变化和癌细胞死亡率,并用有丝分裂完全阻断法分析体内癌细胞的有丝分裂过程。结果ＣＴＸ各剂量组荷瘤小鼠的体重抑制和癌细胞死亡率均有明显的剂量反应关系,与对照组相比有显著的差异（Ｐ＜０．０１）;镜检发现ＣＴＸ能抑制体内癌细胞的有丝分裂,表现在０．４ｍｇ／ｋｇ和０．８ｍｇ／ｋｇ实验组腹水Ｓ１８０细胞处于有丝分裂前期和中期的细胞数量明显减少,其ＭＩ值分别为０．７１％和０．８０％,比对照组显著减少（Ｐ＜０．００１）。结论ＣＴＸ对Ｓ１８０小鼠体内癌细胞的生长有抑制和杀伤作用,并通过干扰和阻断癌细胞的有丝分裂过程,抑制腹水的生长。     

清洁级实验动物四种病毒抗体玻片酶免疫检测试剂盒的研制

本文报道对清洁级实验动物应排除的四种病毒（淋巴细胞脉络丛脑膜炎病毒、小鼠脱脚病病毒、鼠肝炎病毒和仙台病毒）抗体玻片酶免疫（ＥＩＡ）检测试剂盒的研制。四种病毒感染的细胞和对照细胞经冷丙酮固定于载玻片上制成特异性抗原和对照抗原,此四种病毒的抗血清各１０份和ＳＰＦ小鼠血清２０份分别与四种病毒的特异性抗原和对照抗原进行ＥＩＡ交叉试验,结果显示,抗原只与其相应抗血清发生特异性显色反应,与非特异性小鼠血清和ＳＰＦ小鼠血清不显色。与ＨＩ或ＥＬＩＳＡ方法比较,通过对１１２份普通小鼠血清进行测试,结果表明,ＥＩＡ对仙台病毒抗体的检出率（１９．６％）显著高于（＜０．００５）ＨＩ（６．３％）,对小鼠脱脚病病毒抗体的检出率（２３．３％）与ＨＩ（２１．４％）无显著性差异（Ｐ＞０．０５）。ＥＩＡ对淋巴细胞脉络丛脑膜炎病毒和鼠肝炎病毒抗体的检出率分别为１．８％和７１．２％,ＥＬＩＳＡ对两种病毒抗体的检出率分别为１．８％和６７．６％,两种方法对两种病毒抗体的检出率无显著性差异（Ｐ＞０．０５）。重复性试验表明两批四种病毒抗体试剂盒对１０８份小鼠血清两次测定的符合率为９６～１００％。四种病毒的ＥＩＡ抗原在－１８℃保存１２个月或在２－８℃保存３     

蛇毒心脏素对荷瘤小鼠的抗肿瘤作用初步研究

目的 探讨蛇毒心脏毒素（ＣＴＸ）对荷瘤小鼠Ｓ１８０腹水瘤细胞生长抑制的影响。方法 小鼠腹腔接种Ｓ１８０活瘤细胞,连续１０ｄ分别腹腔注ＣＴＸ０．８ｍｋｇ、０．４ｍｇ／ｋｇ、０．２ｍｇ／ｋｇ,分别统计荷瘤小鼠的体重变化和癌细胞死亡率,并用有丝分裂完全民法分析体内癌细胞的有丝分裂过程,结果 ＣＴＸ各剂量组荷瘤小鼠的体重抑制和癌细胞的有丝分裂,表现在０．４ｍｇ／ｋｇ实验组腹水Ｓ１８０细胞处于有丝分裂前期和     

病毒感染后的实验小鼠对植入的肿瘤细胞抑制作用的实验研究

昆明鼠或ＤＢＡ／２鼠腹腔植入Ｓ１８０肉瘤细胞。Ｐ３８８白血病细胞或Ｆｒｉｅｎｄ白血病细胞后１００％死亡。然而在小鼠感染ＰＲ８株甲型流感病毒、ＮＤＶ或Ｍ１４病毒２５天左右的恢复期腹腔接种上述三种恶性肿瘤细胞时,３０～９５％的小鼠能抑制肿瘤发生而存活。另外,自然感染鼠痘而存活的小鼠,在其感染恢复期内接种上述肿瘤细胞,小鼠的存活率可达１００％,而相应的禾感染鼠痘组小鼠１００％死于肿瘤。病毒感染恢复期小鼠的抗肿瘤作用机制是机体非特异性肿瘤免疫机能强化所致。我们的结果表明,病毒恢复期Ｔ细胞的杀肿瘤作用增强并伴有巨噬细胞数量增加及其吞噬活性增加的现象。本研究的结果提示,自然或人为地非致病病毒感染有利于机体清除变异细胞或肿瘤细胞,对肿瘤发生有一定的防护作用。     

甲型流感病毒免疫治疗S34腹水瘤的实验研究

用甲型流感病毒７５－３９株鼠肺适应型,免疫治疗Ｓ３７腹水瘤小鼠,存活率达９３．３％。体外流感病毒感染３７肿瘤细胞,经不同时间观测,到３天时Ｓ３７细胞胎盘蓝染色发现细胞１００％死亡。而对照组Ｓ３７的细胞死亡率为１０％左右。进一步研究病毒免疫治疗Ｓ３７腹水瘤小鼠的机现,发现经病毒感后小鼠ＮＫ杀伤活性升高达５８％,正常鼠ＮＫ活性为２２％,两者有显著性差异。     

空心莲子草口服治疗乳鼠流行性出血热病毒感染的研究

空心莲子草经口服治疗流行性出血热病毒（ＥＨＦＶ）感染的乳鼠。结果显示,５、７．５、１０．０ｍｇ三个剂量组的存活率各为８０％、７２．２％和４０．０％,平均存活天数（ＭＴＤ）为５６．５±０．９、５３．５±１．１和４１．５±２．７ｄ,而病毒对照组的存活率为０．０％,ＭＴＤ为２６．３±０．８ｄ,经该药治疗的感染鼠体内的ＥＨＦＶ抗原表达减少,而未经治疗的感染乳鼠体内的ＥＨＦＶ抗原则在全病程中都显示出较强的表述。治疗组抗病毒效果类似于病毒唑,且口服病毒唑毒性小。说明空心莲子草在体内对ＥＨＦＶ感染鼠有治疗作用。     

家蚕抗菌肽的抗癌作用

从家蚕（Ｂｏｍｂｙｘｍｏｒｉ）免疫蛹血淋巴中提取抗菌肽,以Ｓ１８０荷瘤小鼠和艾氏腹水瘤荷瘤小鼠为模型,研究抗菌肽的抗癌效应,结果表明,抗菌肽明显抑制Ｓ１８０瘤重,３７９２,４５４２和４９８０Ｕ３种剂量抑瘤作用分别为４２．８６％,３９．１３％和３７．８９％,抗菌肽对外周血白细胞数没有影响。病理切片显示,注射抗菌肽荷瘤小鼠癌瘤组织大面积坏死,癌瘤周围组织内有大量炎细胞（单核细胞,中性粒细胞和淋巴细胞）     

E.coli DNA抗肿瘤免疫的动态实验研究

５５只Ｂａｌｂ／ｃ小鼠,５只作为正常对照组,其余５０只荷瘤后随机分为１０组, ５组为 ＴＥＳ对照组, ５组为Ｅ． ｃｏｌｉＤＮＡ治疗组。荷瘤第４ｄ起,分别于治疗组和对照组小鼠皮下注射 ＤＮＡ（１００ｍｇ／Ｌ）或 ＴＥＳ（０． １ｍｏｌ／Ｌ）,０．３ｍｌ／只,隔日１次,共５次。于荷瘤第５,９,１３,１７,２１ｄ处置对照组和治疗组各一组小鼠,进行Ｅ．ｃｏｌｉＤＮＡ抗肿瘤免疫的动态研究。结果表明, Ｅ． ｃｏｌｉ ＤＮＡ体内抑瘤作用出现早、强且持久,主要是通过诱导肿瘤组织坏死所致,它可迅速持久地激活免疫系统,防止出现免疫低下或紊乱;对照组小鼠荷瘤早期可出现暂时的免疫功能增强,随荷瘤时间延长,逐渐降低至较低水平,并出现免疫紊乱。     

Infection with a Mouse-Adapted Strain of the 2009 Pandemic Virus Causes a Highly Severe Disease Associated with an Impaired T Cell Response

Despite a relatively low fatality rate, the 2009 H1N1 pandemic virus differed from other seasonal viruses in that it caused mortality and severe pneumonia in the young and middle-aged population (18–59 years old). The mechanisms underlying this increased disease severity are still poorly understood. In this study, a human isolate of the 2009 H1N1 pandemic virus was adapted to the mouse (MAp2009). The pathogenicity of the MAp2009 virus and the host immune responses were evaluated in the mouse model and compared to the laboratory H1N1 strain A/Puerto Rico/8/1934 (PR8). The MAp2009 virus reached consistently higher titers in the lungs over 14 days compared to the PR8 virus, and caused severe disease associated with high morbidity and 85% mortality rate, contrasting with the 0% death rate in the PR8 group. During the early phase of infection, both viruses induced similar pathology in the lungs. However, MAp2009-induced lung inflammation was sustained until the end of the study (day 14), while there was no sign of inflammation in the PR8-infected group by day 10. Furthermore, at day 3 post-infection, MAp2009 induced up to 10- to 40-fold more cytokine and chemokine gene expression, respectively. More importantly, the numbers of CD4⁺ T cells and virus-specific CD8⁺ T cells were significantly lower in the lungs of MAp2009-infected mice compared to PR8-infected mice. Interestingly, there was no difference in the number of dendritic cells in the lung and in the draining lymph node. Moreover, mice infected with PR8 or MAp2009 had similar numbers of CCR5 and CXCR3-expressing T cells, suggesting that the impaired T cell response was not due to a lack of chemokine responsiveness or priming of T cells. This study demonstrates that a mouse-adapted virus from an isolate of the 2009 pandemic virus interferes with the adaptive immune response leading to a more severe disease.     

Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-κB and JAK-STAT signaling pathway

Influenza viruses, the main cause of respiratory tract diseases, cause high morbidity and mortality in humans. Excessive inflammation in the lungs is proposed to be a hallmark for the severe influenza virus infection, especially influenza A virus infection. Strategies against inflammation induced by influenza A virus infection could be a potential anti-influenza therapy. Here, lethal dose of mouse-adapted H1N1 strain PR8A/PR/8/34 was inoculated C57BL/6 mice to detect the anti-influenza activity of andrographolide, the active component of traditional Chinese medicinal herb Andrographis paniculata, with or without influenza virus entry inhibitor CL-385319. Treatment was initiated on 4 days after infection. The survival rate, body weight, lung pathology, viral loads, cytokine expression were monitored in 14 days post inoculation. The combination group had the highest survival rate. Andrographolide treatment could increase the survival rate, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by infection. Mechanism studies showed the NF-κB and JAK-STAT signaling pathway were involved in the activity of andrographolide. In conclusion, combination of virus entry inhibitor with immunomodulator might be a promising therapeutic approach for influenza.     

Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain

Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection.     

建立小鼠淋巴瘤模型所需环磷酰胺最佳预处理剂量探索

目的:探讨不同剂量环磷酰胺对小鼠肿瘤成模情况的影响,寻找一种简单、有效的建立肿瘤模型的预处理方法。方法:给予BALB/c裸鼠腹腔注射不同剂量环磷酰胺,72小时后再给予小鼠皮下接种淋巴瘤细胞,观察预处理前后小鼠外周血白细胞数量及体重变化情况,以及肿瘤成模率、急性死亡率等。结果:①组1(NS对照组)、组2(100mg/kg×1d)、组3(125mg/kg×1d)、组4(75mg/kg×2d)预处理后体重较处理前无显著性变化,亦无急性死亡情况发生;而组5(125mg/kg×2d)、组6(200mg/kg×2d)、组7(125mg/kg×3d)、组8(250mg/kg×3d)小鼠体重较预处理前明显减轻,且急性死亡率依次为30%、58.3%、50%、75%;②组1和组2小鼠预处理后72小时外周血白细胞数较处理前无明显差异,同时均未成模;而组3、组4、组5、组6、组7、组8小鼠白细胞较预处理前均显著下降,成模率依次为20%、83.3%、60%、33.3%、50%、25%。结论:使用环磷酰胺75mg/kg连续2天腹腔注射的预处理方案,操作简单,成本低廉,通过观察外周血白细胞数和小鼠体重水平等指标即可初步判断建模情况,同时肿瘤成模率高,毒副作用小,是理想的预处理方案。     

In Vivo Antiviral Activity of 1,3-Bis(2-Chloroethyl)-1-Nitrosourea

A prolongation in the lives of Swiss mice inoculated intracerebrally with lymphocytic choriomeningitis virus (LCM) was observed after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). A variety of treatment schedules, including therapy once or twice daily up to 17 days and single treatments at various times after virus inoculation, were employed. Virus titers ranging to greater than 10⁴ were detected in the blood and brains of surviving drug-treated animals. In three comparative studies in which different treatment schedules were used, BCNU was shown to exert a protective effect approximately equal to that of methotrexate in LCM virus-infected mice. Tests were also carried out to investigate the activity of BCNU in mice experimentally infected with eastern equine encephalomyelitis (EEE) virus, western equine encephalomyelitis virus, Semliki Forest (SF) virus, herpes simplex virus, influenza virus strain PR8, vaccinia virus strain WR, Rous sarcoma virus, Friend leukemia virus (FLV), and poliovirus. Slight increases in life span were observed in the treated EEE, SF, and influenza PR8 virus-infected animals. Significant reduction in splenomegaly in FLV-infected animals treated with BCNU was demonstrated. The possible mechanisms of LCM virus inhibition by BCNU, on the basis of these and other studies, were postulated to be either specific antiviral activity or inhibition of “lethal” immune response to the LCM virus. Each of these postulates is discussed.     

小鼠对仙台病毒Tianjin株易感性研究

研究129Sv、DBA/2、Kunming、BALB/c四种小鼠对仙台病毒Tianjin株的感染特点,并通过观察易感性的不同,确定适于研究此病毒致病性及疫苗的小型啮齿类实验动物。用9～11d龄鸡胚接种仙台病毒Tianjin株,72h后收集尿囊腔内效价为1:1 280病毒液,用5μl和6倍稀释的30μl病毒液分别接种129Sv、DBA/2、Kunming、BALB/c小鼠,观查12d小鼠体重变化,计算生存率。用6倍稀释的30μl病毒液接种Kunming、BALB/c小鼠,于接种前第1天以及接种后第4、7天断颈处死,取左肺制成切片,HE染色观察病理改变,综合判断仙台病毒Tianjin株对四种鼠感染的易感性的不同。129Sv、DBA/2小鼠在接种仙台病毒Tianjin株5μl后,最高平均体重下降分别为13.0%、4.7%,四种鼠12d生存率均为100%;接种稀释的30μl病毒液,129Sv、DBA/2、Kunming、BALB/c最高平均体重下降21.7%、30.3%、16.7%、9.6%;12d生存率分别为20%、0%、80%、100%。Kunming鼠在感染后第4、7d的肺组织病理改变较BALB/c严重,表现为大量炎细胞渗出,粘膜下层实质性增厚。以上实验结果表明DBA/2对仙台病毒Tianjin株感染最易感,BALB/c耐受性最强,易感顺序为DBA/2129SvKunmingBALB/c。DBA/2和129Sv小鼠可作为仙台病毒Tianjin株致病性及疫苗研究的首选实验动物。     

The Effect of Tamoxifen on Expression of ER,PR, Cerb-B2, and ki-67 in C3H Mice Spontaneous Breast Cancer Model and The Relation with Chemotherapeutic Effect

To explore the effect of tamoxifen on expression of ER, PR, Cerb-B2, and ki-67 in C3H mice spontaneous breast cancer model and further explore its relation with chemotherapeutic effect. Forty male C3H mice with spontaneous breast cancer aged 10 months were selected, and randomly divided into model group and tamoxifen group, with 20 mice in either group. Model group received intraperitoneal injection of normal saline, tamoxifen group received 5 mg/Kg tamoxifen injection. Tumor volume was measured every 3 days for 12 days in total. After that the mice were killed to weigh the tumor for tumor growth inhibition rate calculation; breast cancer specimen was collected, and immunohistochemistry was used to detect ER, PR, Cerb-B2, and ki-67 positive cells, western blot was used to detect expression of ER, PR, Cerb-B2, and ki-67 in breast cancer. The tumor growth inhibition rate of tamoxifen on mice was 61.56 %. Compared with model group, tumor weight in mice from tamoxifen group was significantly lower, tumor growth rate in tamoxifen group was significantly lower than model group; immunohistochemical staining results showed that compared with model group, ER, PR, Cerb-B2, and ki-67 positive cells in tumor of tamoxifen group were significantly lower (P < 0.05). Among them, ki-67 expression in tamoxifen group was negative; western blot semi-quantitative results were in accordance with immunohistochemistry results. Tamoxifen is effective on C3H mice spontaneous breast cancer. After being treated with tamoxifen, expression levels of ER, PR, Cerb-B2 and ki-67 are changed, and change of ER, PR, Cerb-B2, and ki-67 can predict the therapeutical effect of tamoxifen.     

恶性横纹肌样瘤（MRT）的起源研究——高变异率HeLa细胞致裸鼠产生MRT的实验研究

HeLa细胞KB株、X株、NM20／X株、H株的染色体众数依次为60±3（超二倍体）、62±3（超二倍体）、68±3（超二倍体和亚四倍体）和78±2（亚四倍体）,所占比率分别为72%～76%,69%,52%和40%。在纯化3代的肿瘤阴性对照二倍体猫肾（染色体众数38所占比率80%）和犬肾原代细胞皮下接种裸鼠的致癌／致瘤率分别为0%（0／22）和0%（0／10）,X株HeLa细胞冻融裂解物皮下接种裸鼠产生进行性缩小肿瘤的比率为20%（1／5）的前提下,HeLa细胞KB株、X株、NM20／X株皮下接种裸鼠产生进行性生长恶性肿瘤的比率分别为100%（10／ 10）,100%（25／25）和100%（5／5）,H株细胞皮下接种裸鼠产生恶性肿瘤的比率为50%（5／10）。其中,只有HeLa细胞KB株10～11代（染色体结构畸变率高达20%,出现18%双着丝点和2%断片）以超高数量接种的1组4只裸鼠（0.17ml12.75×10     

Immunosuppression induced by respiratory viruses (influenza virus, adenovirus) in mice

The influence of respiratory viruses (adenovirus, influenza virus) on humoral immune response to heterologous T-dependent and T-independent antigens was studied. It was shown that inoculation of mice by the influenza virus (A/PR8/34-A/PR/8) 3 days before sheep red blood cells administration led to the inhibition of antibody forming cell (AFC) and immunoglobulin, forming cell (IFC) increase on 69% and 59% respectively. Adenovirus type 6 induced the similar suppression of AFC and IFC formation. Thus, viruses induced immuno-suppression, which was polyclonal. It was also shown that virus of one strain (type) could inhibit immune response to another strain (type) of virus. The immune response to T-independent antigen was not suppressed. The virus-induced immunosuppression was dependent on: 1) the infectivity of respiratory viruses, 2) the route of virus and heterologous antigen injection, and 3) the interval between the viruses and antigen inoculation.     

Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice.

The ability of monoclonal antibodies (MAbs) to passively cure an influenza virus pneumonia in the absence of endogenous T- and B-cell responses was investigated by treating C.B-17 mice, homozygous for the severe combined immunodeficiency (SCID) mutation, with individual monoclonal antiviral antibodies 1 day after pulmonary infection with influenza virus PR8 [A/PR/8/34 (H1N1)]. Less than 10% of untreated SCID mice survived the infection. By contrast, 100% of infected SCID mice that had been treated with a single intraperitoneal inoculation of at least 175 micrograms of a pool of virus-neutralizing (VN+) antihemagglutinin (anti-HA) MAbs survived, even if antibody treatment was delayed up to 7 days after infection. The use of individual MAbs showed that recovery could be achieved by VN+ anti-HA MAbs of the immunoglobulin G1 (IgG1), IgG2a, IgG2b, and IgG3 isotypes but not by VN+ anti-HA MAbs of the IgA and IgM isotypes, even if the latter were used in a chronic treatment protocol to compensate for their shorter half-lives in vivo. Both IgA and IgM, although ineffective therapeutically, protected against infection when given prophylactically, i.e., before exposure to virus. An Fc gamma-specific effector mechanism was not an absolute requirement for antibody-mediated recovery, as F(ab')2 preparations of IgGs could cure the disease, although with lesser efficacy, than intact IgG. An anti-M2 MAb of the IgG1 isotype, which was VN- but bound well to infected cells and inhibited virus growth in vitro, failed to cure. These observations are consistent with the idea that MAbs of the IgG isotype cure the disease by neutralizing all progeny virus until all productively infected host cells have died. VN+ MAbs of the IgA and IgM isotypes may be ineffective therapeutically because they do not have sufficient access to all tissue sites in which virus is produced during influenza virus pneumonia.