免疫學(xué)，腫瘤免疫治療，體液免疫，抗體作用機(jī)制和優(yōu)化，B淋巴細(xì)胞發(fā)育分化
體液免疫與治療實(shí)驗(yàn)室的研究主要有兩個(gè)方向：(一)腫瘤免疫治療抗體作用規(guī)律和優(yōu)化策略,；（二）B淋巴細(xì)胞的發(fā)育調(diào)控機(jī)制。
腫瘤免疫治療
腫瘤的免疫治療是過(guò)去十年取得的最有希望的科學(xué)進(jìn)步之一，被《科學(xué)》雜志評(píng)選為2013年“年度突破”,。目前主要有四種手段可以利用免疫系統(tǒng)的力量來(lái)對(duì)抗腫瘤：1）針對(duì)腫瘤抗原的抗體被輸入到腫瘤病人體內(nèi)殺滅腫瘤細(xì)胞，其中部分機(jī)制是腫瘤細(xì)胞結(jié)合了抗體之后被表達(dá)Fc受體的免疫細(xì)胞殺滅,；2）從腫瘤病人分離的抗腫瘤免疫細(xì)胞在體外擴(kuò)增（有時(shí)候還被基因修飾）,，然后回輸?shù)讲∪梭w內(nèi)發(fā)揮抗腫瘤作用；3）T細(xì)胞被基因工程修飾后表達(dá)識(shí)別腫瘤抗原的嵌合抗原受體（Chimeric Antigen Receptor，CAR）被輸入到腫瘤病人體內(nèi),；4）利用單克隆抗體（單抗）阻斷限制免疫細(xì)胞活性的免疫抑制信號(hào)通路（被稱為“節(jié)點(diǎn)”）從而提高免疫細(xì)胞的活性,。
激動(dòng)型抗體:一類具有廣泛前景的腫瘤免疫治療抗體
體液免疫與治療實(shí)驗(yàn)室的一個(gè)主要研究興趣是激動(dòng)型腫瘤免疫治療抗體的作用規(guī)律和優(yōu)化策略。已經(jīng)研發(fā)成功的腫瘤免疫治療藥物包括抗CTLA-4與抗PD-1/PD-L1 抗體,，它們都通過(guò)阻斷免疫細(xì)胞表面?zhèn)鬟f免疫抑制信號(hào)的分子的作用增強(qiáng)免疫系統(tǒng)針對(duì)腫瘤細(xì)胞產(chǎn)生的殺傷性T細(xì)胞應(yīng)答從而殺傷腫瘤,，屬于阻斷型抗體。而除此之外,，還有一類被稱為“激動(dòng)型抗體”的腫瘤免疫治療手段,，能夠通過(guò)結(jié)合免疫細(xì)胞表面?zhèn)鬟f免疫激活信號(hào)的靶標(biāo)分子并激活其控制的重要免疫激活信號(hào)通路，進(jìn)而增強(qiáng)抗腫瘤免疫應(yīng)答間接殺死腫瘤細(xì)胞,。然而,，雖然激動(dòng)型腫瘤免疫治療抗體已經(jīng)在動(dòng)物模型中證明了其巨大潛力，并且已經(jīng)成為一個(gè)被廣泛接受并看好的腫瘤免疫治療理念,，這類抗體的研發(fā)至今尚未成功,，是腫瘤免疫治療領(lǐng)域當(dāng)前的一個(gè)主要挑戰(zhàn)。糾其原因,，可能與這類抗體的體內(nèi)作用條件不明有關(guān),。在基于鼠類激動(dòng)型抗腫瘤抗體的研究中，我們發(fā)現(xiàn)了一條可能有助于研發(fā)具有較好抗腫瘤活性的激動(dòng)型抗體的線索,，即這些抗體的Fcγ受體（Fcγ receptor,，或FcγR）結(jié)合能力對(duì)它們的抗腫瘤活性具有決定性的影響，現(xiàn)在正在展開研究,。
Fcγ受體的體液免疫與治療調(diào)控功能
Fcγ受體與IgG抗體相互作用,，是IgG抗體治療作用的重要介導(dǎo)者和調(diào)控者；同時(shí),，F(xiàn)cγ受體與含有IgG的免疫復(fù)合物相互作用,，調(diào)控免疫應(yīng)答的傳入和傳出，如對(duì)B細(xì)胞應(yīng)答的調(diào)控,。Fcγ受體廣泛表達(dá)在免疫細(xì)胞表面,，介導(dǎo)抗體的免疫調(diào)控和效應(yīng)功能。人和小鼠的FcγR家族都由幾個(gè)活化性FcγRs（activating FcγRs）和一個(gè)抑制性Fcγ受體（Inhibitory FcγRIIB,，或FcγRIIB）組成（圖1）,。抑制性Fcγ受體胞內(nèi)區(qū)含有酪氨酸依賴的抑制型基序（Immunoreceptor Tyrosine-based Inhibitory Motif，或ITIM）傳遞抑制信號(hào),，起抑制細(xì)胞激活的作用,。活化性FcγRs通過(guò)含有酪氨酸依賴的激活型基序（Immunoreceptor Tyrosine-based Activation Motif,，或ITAM)的胞內(nèi)區(qū)或Fc受體γ鏈(Fc receptor γ chain)傳遞活化信號(hào),，促進(jìn)細(xì)胞激活。大量的實(shí)驗(yàn)已經(jīng)證明活化性FcγRs在IgG抗體的效應(yīng)功能中發(fā)揮主導(dǎo)作用。例如,，抗體依賴細(xì)胞介導(dǎo)的細(xì)胞毒性作用（Antibody-Dependent Cell-Mediated Cytotoxicity,，或ADCC）就是通過(guò)活化性FcγRs完成的。ADCC是效應(yīng)型治療抗體重要的腫瘤殺傷機(jī)制,，對(duì)這類抗體（如Rituximab）的療效有顯著影響,。
我們發(fā)現(xiàn)抑制性Fcγ受體能夠?qū)Χ喾N免疫細(xì)胞的調(diào)控對(duì)免疫耐受的維持都具有顯著影響(Li et al. 2014. Journal of Immunology 192(7):3021-8.)，如在B細(xì)胞與樹突狀細(xì)胞（dendritic cells）中特異敲除抑制性Fcγ受體致使小鼠在CIA(collagen induced arthritis)自身免疫模型中更加敏感（圖2）.此外,，人類抑制性Fcγ受體的功能受損被發(fā)現(xiàn)與包括系統(tǒng)性紅斑狼瘡,、風(fēng)濕性關(guān)節(jié)炎等多種自身免疫疾病。
我們還系統(tǒng)研究了Fc-FcγRs相互作用對(duì)激動(dòng)型抗TNF受體超家族成員抗體（agonistic anti-TNFR antibodies）分子的體內(nèi)活性的影響,。以激動(dòng)型抗CD40和DR5抗體為例,，我們發(fā)現(xiàn)這類抗體的體內(nèi)活性依賴于Fcγ受體分子，而且抗體Fc的屬性對(duì)其體內(nèi)抗腫瘤活性具有決定性的影響（圖3）,。
進(jìn)一步研究表明,，與依賴于活化性Fcγ受體的效應(yīng)型抗體不同，激動(dòng)型抗TNFR抗體體內(nèi)活性只依賴于抑制性Fcγ受體,，而與活化性FcγRs的相互作用會(huì)降低其活性,。在此基礎(chǔ)上，我們提出了一種優(yōu)化激動(dòng)型抗TNFR超家族成員抗體的方法（圖4）
：最大化與抑制性Fcγ受體的結(jié)合親和力,，同時(shí)最小化與活化性FcγRs的結(jié)合親和力,，和傳統(tǒng)的優(yōu)化效應(yīng)型抗體的方法剛好相反。用這種方法優(yōu)化的人抗小鼠CD40抗體都已經(jīng)在人抑制性Fcγ受體轉(zhuǎn)基因小鼠模型中得到了驗(yàn)證（圖5）,。
這些成果被連續(xù)發(fā)表在包括2011年Science（Li, F., and J.V. Ravetch. 2011. Science 333:1030-1034），2012年P(guān)NAS雜志（Li, F., and J.V. Ravetch. 2012. Proceedings of the National Academy of Sciences of the United States of America 109:10966-71）,，和2013年P(guān)NAS雜志（Li, F., and J.V. Ravetch. 2013. Proceedings of the National Academy of Sciences of the United States of America 110:19501-6）,，和2016年Cancer Cell雜志（Dahan, R., B. C. Barnhart, F. Li, A. P. Yamniuk, A. Korman, J.V. Ravetch. 2016. Cancer Cell），并受邀在Cell Cycle雜志上就這一研究領(lǐng)域的進(jìn)展發(fā)表評(píng)論文章（Li, F., and J.V. Ravetch. 2012. Cell cycle 11:18）,。這些研究結(jié)果為解釋尚未成功的激動(dòng)型抗TNFR抗體研發(fā)提供了一條線索,，可能有利于研發(fā)基于這類抗體的抗腫瘤藥物。
目前,，實(shí)驗(yàn)室工作的重點(diǎn)是進(jìn)一步研究腫瘤免疫治療抗體作用規(guī)律和優(yōu)化策略,，包括Fcγ受體相關(guān)和其它的調(diào)控規(guī)律和策略；同時(shí),，實(shí)驗(yàn)室對(duì)B淋巴細(xì)胞的發(fā)育調(diào)控規(guī)律也非常感興趣,，正在開展Fcγ受體及相關(guān)分子對(duì)體液免疫的調(diào)控機(jī)制。
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