2-涓欏熀鍜攽锛氭柊鍨嬬柅鑻椾綈鍔戠殑鏄庢槦鎴愬垎

鍦ㄧ暥(d膩ng)浠婂叏鐞冨叕鍏辫(w猫i)鐢熼牁(l菒ng)鍩�锛岀柅鑻楃殑鐮旂櫦(f膩)鍜屾噳(y墨ng)鐢ㄧ劇鐤戞槸鎳�(y墨ng)灏嶅悇绋偝鏌撶梾鐨勯棞(gu膩n)閸垫墜娈典箣涓€銆傜劧鑰�锛岄毃钁椾汉鍊戝皪鐤嫍瀹夊叏鎬у拰鏈夋晥鎬х殑瑕佹眰瓒婁締瓒婇珮锛屽偝绲�(t菕ng)鐤嫍浣愬姂宸茬稉(j墨ng)闆ｄ互婊胯冻鐝�(xi脿n)浠ｉ啱(y墨)瀛�(xu茅)鐨勯渶姹�銆傜偤浜嗘彁楂樼柅鑻楃殑鍏嶇柅鍘熸€э紝绉戝(xu茅)瀹跺€戜笉鏂锋帰绱㈡柊鐨勪綈鍔戞潗鏂�锛屽叾涓紝2-涓欏熀鍜攽锛�2-Propylimidazole, 2-PI锛変綔鐐轰竴绋柊鑸堢殑鏈夋(j墨)鍖栧悎鐗�锛岄€愭几宥勯湶闋锛屾垚鐐虹柅鑻椾綈鍔戠爺绌剁殑鐔遍粸銆�

2-涓欏熀鍜攽鏄竴绋叿鏈夌崹鐗瑰寲瀛�(xu茅)绲�(ji茅)妲�(g貌u)鐨勫皬鍒嗗瓙鍖栧悎鐗�锛屽叾鍒嗗瓙寮忕偤C6H10N2銆傞€欑ó鍖栧悎鐗╀笉鍍呭叿鏈夎壇濂界殑鐢熺墿鐩稿鎬�锛岄倓鑳介€氶亷澶氱ó姗�(j墨)鍒跺寮�(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)銆傝繎骞翠締锛屽湅鍏�(n猫i)澶栫殑鐮旂┒琛ㄦ槑锛�2-涓欏熀鍜攽鍦ㄧ柅鑻椾綈鍔戜腑鐨勬噳(y墨ng)鐢ㄥ墠鏅唬闂婏紝灏ゅ叾鏄湪鎻愬崌鐤嫍鐨勫厤鐤晥鏋�銆佹笡灏戝壇浣滅敤绛夋柟闈㈣〃鐝�(xi脿n)鍑轰簡椤憲鐨勫劒(y艒u)鍕€€�

鏈枃灏囨繁鍏ユ帰瑷�2-涓欏熀鍜攽鍦ㄦ柊鍨嬬柅鑻椾綈鍔戦厤鏂逛腑鐨勬噳(y墨ng)鐢ㄥ強鍏跺厤鐤(di脿o)绡€(ji茅)鏁堟灉锛岀祼(ji茅)鍚堟柊鐨勭爺绌舵垚鏋滃拰瀵﹂殯妗堜緥锛屽公鍔╄畝鑰呭叏闈簡瑙ｉ€欎竴鍓嶆部闋�(l菒ng)鍩熺殑鏂伴€�(j矛n)灞�銆傛枃绔犲皣鍒嗙偤浠ヤ笅骞惧€嬮儴鍒嗭細2-涓欏熀鍜攽鐨勫熀鏈壒鎬с€佷綔鐐虹柅鑻椾綈鍔戠殑浣滅敤姗�(j墨)鍒�銆佽垏鍏朵粬浣愬姂鐨勬瘮杓冨劒(y艒u)鍕�銆佽嚚搴婅│椹楃祼(ji茅)鏋�銆佷互鍙婃湭渚嗙殑鐧�(f膩)灞曟柟鍚�銆傚笇鏈涢€氶亷鏈枃鐨勪粙绱癸紝鑳藉鐐哄緸浜嬬柅鑻楃爺鐧�(f膩)鐨勭鐮斾汉鍝″拰灏嶇柅鑻楁劅鑸堣叮鐨勮畝鑰呮彁渚涙湁鍍瑰€肩殑鍙冭€�銆�

2-涓欏熀鍜攽鐨勫熀鏈壒鎬�

2-涓欏熀鍜攽锛�2-Propylimidazole, 2-PI锛夋槸涓€绋湁姗�(j墨)鍖栧悎鐗╋紝灞簬鍜攽椤炶鐢熺墿銆傚畠鐨勫垎瀛愬紡鐐篊6H10N2锛屽垎瀛愰噺鐐�114.16 g/mol銆�2-PI鐨勫寲瀛�(xu茅)绲�(ji茅)妲�(g貌u)鐢变竴鍊嬪挭鍞戠挵(hu谩n)鍜屼竴鍊嬩笝鍩哄伌(c猫)閺堢祫鎴�锛岄€欑ó鐛ㄧ壒鐨勭祼(ji茅)妲�(g貌u)璩︿簣浜嗗畠涓€绯诲垪鍎�(y艒u)鐣扮殑鐗╃悊鍜屽寲瀛�(xu茅)鎬ц唱(zh矛)锛屼娇鍏跺湪鐢熺墿閱�(y墨)钘ラ牁(l菒ng)鍩熷叿鏈夊唬娉涚殑鎳�(y墨ng)鐢ㄦ經鍔涖€�

1. 鐗╃悊鎬ц唱(zh矛)

2-涓欏熀鍜攽鐨勭墿鐞嗘€ц唱(zh矛)濡備笅琛ㄦ墍绀猴細

2-PI鐨勪綆鐔旈粸鍜岄珮娌搁粸浣垮緱瀹冨湪甯告韩涓嬪憟娑叉厠(t脿i)锛屼究浜庡姞宸ュ拰铏曠悊銆傛澶�锛屽畠鍦ㄦ按鍜屽叾浠栨サ鎬ф憾鍔戜腑鍏锋湁鑹ソ鐨勬憾瑙ｆ€�锛岄€欑偤鍏跺湪鐤嫍閰嶆柟涓殑鎳�(y墨ng)鐢ㄦ彁渚涗簡渚垮埄姊濅欢銆傜壒鍒ユ槸鍦ㄥ埗鍌欐按鎬х柅鑻楁檪锛�2-PI鍙互杓曟澗鍦拌垏鎶楀師鍜屽叾浠栬紨鏂欐贩鍚堬紝褰㈡垚绌�(w臎n)瀹氱殑鎳告诞娑叉垨涔冲姂銆�

2. 鍖栧(xu茅)鎬ц唱(zh矛)

2-涓欏熀鍜攽鐨勫寲瀛�(xu茅)鎬ц唱(zh矛)涓昏楂旂従(xi脿n)鍦ㄥ叾鍜攽鐠�(hu谩n)鍜屼笝鍩哄伌(c猫)閺堜笂銆傚挭鍞戠挵(hu谩n)鏄竴鍊嬩簲鍏冮洔鐠�(hu谩n)锛屽惈鏈夊叐鍊嬫爱鍘熷瓙锛屽叿鏈夎純寮�(qi谩ng)鐨勫牽鎬у拰閰嶄綅鑳藉姏銆傚畠鍙互鑸囬噾灞洟瀛�銆佽泲鐧借唱(zh矛)绛夌敓鐗╁ぇ鍒嗗瓙鐧�(f膩)鐢熺浉浜掍綔鐢�锛屽緸鑰屽奖闊跨窗(x矛)鑳炲収(n猫i)鐨勪俊铏熷偝灏�(d菐o)鍜屽厤鐤弽鎳�(y墨ng)銆備笝鍩哄伌(c猫)閺堝墖璩︿簣浜�2-PI涓€瀹氱殑鐤忔按鎬�锛屼娇鍏惰兘澶犲湪鑴傝唱(zh矛)楂�銆佸井鐞冪瓑杓夐珨涓┅(w臎n)瀹氬瓨鍦�锛屽欢闀疯棩鐗╃殑閲嬫斁鏅傞枔銆�

2-PI鐨勫寲瀛�(xu茅)绌�(w臎n)瀹氭€ц純楂�锛屽湪甯告韩涓嬩笉鏄撳垎瑙ｆ垨璁婅唱(zh矛)锛屼絾鍦ㄥ挤(qi谩ng)閰�銆佸挤(qi谩ng)鍫挎垨楂樻韩姊濅欢涓嬪彲鑳芥渻鐧�(f膩)鐢熸按瑙ｆ垨姘у寲鍙嶆噳(y墨ng)銆傚洜姝わ紝鍦ㄥ劜瀛樺拰浣跨敤閬庣▼涓�锛屾噳(y墨ng)閬垮厤鎺ヨЦ妤电鐠�(hu谩n)澧�锛屼互纰轰繚鍏舵€ц兘鐨勭┅(w臎n)瀹氭€с€�

3. 鐢熺墿鐩稿鎬�

2-涓欏熀鍜攽鐨勭敓鐗╃浉瀹规€ф槸鍏朵綔鐐虹柅鑻椾綈鍔戠殑閲嶈鍎�(y艒u)鍕箣涓€銆傜爺绌惰〃鏄庯紝2-PI灏嶅摵涔冲嫊鐗╃窗(x矛)鑳炲叿鏈夎純浣庣殑姣掓€�锛屼笉鏈冨紩璧锋槑椤殑绱�(x矛)鑳炴悕鍌锋垨鐐庣櫏鍙嶆噳(y墨ng)銆傚湪灏忛紶銆佸ぇ榧犲拰闈炰汉闈堥暦椤炲嫊鐗╃殑楂斿収(n猫i)瀵﹂涓�锛�2-PI鐨勫崐鏁�(sh霉)鑷存鍔戦噺锛圠D50锛夐仩(yu菐n)楂樹簬甯哥敤鍔戦噺锛岄’绀哄嚭鑹ソ鐨勫畨鍏ㄦ€�銆�

姝ゅ锛�2-PI鍙互閫氶亷浠ｈ瑵閫斿緫杩呴€熻姗�(j墨)楂旈檷瑙ｇ偤鐒″鐨勪唬璎濈敘(ch菐n)鐗�锛岀祩鎺掑嚭楂斿銆傞€欐剰鍛宠憲鍗充娇鍦ㄩ暦鏈熶娇鐢ㄧ殑鎯呮硜涓嬶紝2-PI涔熶笉鏈冨湪楂斿収(n猫i)绌嶇疮锛屾笡灏戜簡娼涘湪鐨勪笉鑹弽鎳�(y墨ng)棰�(f膿ng)闅�銆傞€欎竴鐗规€т娇寰�2-PI鎴愮偤涓€绋悊鎯崇殑鐤嫍浣愬姂鍊欓伕鐗�锛屽挨鍏堕仼鐢ㄤ簬闇€瑕佸娆℃帴绋殑鐤嫍銆�

4. 鍚堟垚鏂规硶

2-涓欏熀鍜攽鐨勫悎鎴愭柟娉曠浉灏嶇啊鍠�锛岄€氬父閲囩敤鍜攽鑸囦笝鍩洪沟鍖栫墿锛堝婧翠笝鐑凤級鍦ㄥ偓鍖栧姂浣滅敤涓嬬殑瑕牳鍙栦唬鍙嶆噳(y墨ng)渚嗗埗鍌欍€備互涓嬫槸2-PI鐨勪竴绋父瑕嬪悎鎴愯矾绶氾細

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2. 鍌寲鍔戞坊鍔�锛氬姞鍏ュ皯閲忕殑鍫挎€у偓鍖栧姂锛堝姘哀鍖栭墍鎴栫⒊閰搁墍锛�锛屼互淇冮€�(j矛n)鍙嶆噳(y墨ng)閫�(j矛n)琛�銆�
3. 鍔犵啽鍥炴祦锛氬皣鍙嶆噳(y墨ng)楂旂郴鍔犵啽鑷抽仼鐣�(d膩ng)婧害锛堥€氬父鐐�80-100掳C锛�锛屽苟淇濇寔鍥炴祦鐙€鎱�(t脿i)鏁�(sh霉)灏忔檪銆�
4. 鍒嗛洟绱斿寲锛氬弽鎳�(y墨ng)绲�(ji茅)鏉熷悗锛岄€氶亷钂搁ぞ銆佹煴灞ゆ瀽绛夋柟娉曞垎闆㈠嚭鐩(bi膩o)鐢�(ch菐n)鐗�2-PI锛屽苟閫�(j矛n)琛岀磾搴︽娓�銆�

閫氶亷涓婅堪鏂规硶锛屽彲浠ラ珮鏁堝湴鍚堟垚楂樼磾搴︾殑2-涓欏熀鍜攽锛屾豢瓒冲ぇ瑕�(gu墨)妯＄敓鐢�(ch菐n)鐨勯渶瑕�銆傛澶栵紝鐮旂┒浜哄摗閭勫彲浠ラ€氶亷瑾�(di脿o)鏁村弽鎳�(y墨ng)姊濅欢鎴栧紩鍏ュ叾浠栧畼鑳藉湗(tu谩n)锛岄€�(j矛n)涓€姝ュ劒(y艒u)鍖�2-PI鐨勬€ц兘锛屼互閬╂噳(y墨ng)涓嶅悓鐨勬噳(y墨ng)鐢ㄥ牬鏅€�

2-涓欏熀鍜攽浣滅偤鐤嫍浣愬姂鐨勪綔鐢ㄦ(j墨)鍒�

2-涓欏熀鍜攽锛�2-PI锛変綔鐐轰竴绋柊鍨嬬殑鏈夋(j墨)鍖栧悎鐗�锛屽湪鐤嫍浣愬姂涓殑鎳�(y墨ng)鐢ㄤ箣鎵€浠ュ倷鍙楅棞(gu膩n)娉紝涓昏鏄洜鐐哄畠鑳藉閫氶亷澶氱ó姗�(j墨)鍒堕’钁楀寮�(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)銆傝垏鍌崇当(t菕ng)鐨勯媮楣戒綈鍔戠浉姣�锛�2-PI涓嶅儏鑳藉婵€娲诲厛澶╁厤鐤郴绲�(t菕ng)锛岄倓鑳借(di脿o)绡€(ji茅)閬╂噳(y墨ng)鎬у厤鐤弽鎳�(y墨ng)锛屽緸鑰屾彁楂樼柅鑻楃殑淇濊(h霉)鏁堝姏銆傛帴涓嬩締锛屾垜鍊戝皣瑭崇窗(x矛)鎺㈣◣2-PI浣滅偤鐤嫍浣愬姂鐨勫叿楂斾綔鐢ㄦ(j墨)鍒�銆�

1. 婵€娲诲厛澶╁厤鐤郴绲�(t菕ng)

鍏堝ぉ鍏嶇柅绯荤当(t菕ng)鏄(j墨)楂旀姷寰＄梾鍘熼珨鐨勯亾闃茬窔锛屼富瑕佸寘鎷法鍣窗(x矛)鑳炪€佹ü绐佺媭绱�(x矛)鑳烇紙DCs锛�銆佽嚜鐒舵鍌风窗(x矛)鑳烇紙NK绱�(x矛)鑳烇級绛夊厤鐤窗(x矛)鑳炪€�2-PI閫氶亷鑸囬€欎簺鍏嶇柅绱�(x矛)鑳炶〃闈㈢殑妯″紡璀樺垾鍙楅珨锛圥RRs锛夌祼(ji茅)鍚�锛岃Ц鐧�(f膩)涓€绯诲垪淇¤櫉閫氳矾锛岄€�(j矛n)鑰屾縺娲诲厛澶╁厤鐤弽鎳�(y墨ng)銆�

1.1 TLR淇¤櫉閫氳矾鐨勬縺娲�

2-PI鑳藉鐗圭暟鎬у湴婵€娲籘oll妯ｅ彈楂旓紙TLRs锛夛紝灏ゅ叾鏄疶LR4鍜孴LR7/8銆俆LRs鏄竴椤為噸瑕佺殑PRRs锛岃兘澶犺瓨鍒ョ梾鍘熼珨鐩搁棞(gu膩n)鐨勫垎瀛愭ā寮忥紙PAMPs锛�锛屽苟鍦ㄦ劅鏌撳垵鏈熻繀閫熷暉鍕曞厤鐤弽鎳�(y墨ng)銆傜暥(d膩ng)2-PI鑸嘥LR4绲�(ji茅)鍚堟檪锛屾渻婵€娲籑yD88渚濊炒鐨勪俊铏熼€氳矾锛屽皫(d菐o)鑷碞F-魏B鐨勬椿鍖�锛岄€�(j矛n)鑰屼績閫�(j矛n)淇冪値鍥犲瓙锛堝TNF-伪銆両L-6銆両L-1尾锛夌殑鍒嗘硨銆傞€欎簺淇冪値鍥犲瓙涓嶅儏鑳藉澧炲挤(qi谩ng)灞€閮ㄧ値鐧ュ弽鎳�(y墨ng)锛岄倓鑳芥嫑鍕熸洿澶氱殑鍏嶇柅绱�(x矛)鑳炲埌鎰熸煋閮ㄤ綅锛屽姞閫熺梾鍘熼珨鐨勬竻闄ゃ€�

鍙︿竴鏂归潰锛�2-PI鑸嘥LR7/8鐨勭祼(ji茅)鍚堝墖鏈冩縺娲籌(l菒ng)RF7渚濊炒鐨勪俊铏熼€氳矾锛岃獦灏�(d菐o)I鍨嬪共鎿剧礌锛圛FN-伪/尾锛夌殑鐢�(ch菐n)鐢熴€侷鍨嬪共鎿剧礌鍏锋湁寤ｈ瓬鐨勬姉鐥呮瘨娲绘€�锛岃兘澶犳姂鍒剁梾姣掑京(f霉)鍒�锛屽悓鏅傞倓鑳藉寮�(qi谩ng)DCs鐨勬姉鍘熸彁鍛堣兘鍔涳紝淇冮€�(j矛n)T绱�(x矛)鑳炵殑娲诲寲銆�

1.2 NLRP3鐐庢€у皬楂旂殑婵€娲�

闄や簡TLRs锛�2-PI閭勮兘澶犳縺娲籒OD妯ｅ彈楂旇泲鐧�3锛圢LRP3锛夌値鎬у皬楂�銆侼LRP3鐐庢€у皬楂旀槸涓€绋铔嬬櫧寰�(f霉)鍚堢墿锛屽弮鑸囪(di脿o)鎺х値鐧ュ弽鎳�(y墨ng)鐨勯棞(gu膩n)閸电挵(hu谩n)绡€(ji茅)銆傜暥(d膩ng)2-PI鑸嘚LRP3绲�(ji茅)鍚堟檪锛屾渻灏�(d菐o)鑷碿aspase-1鐨勬椿鍖�锛岄€�(j矛n)鑰屽垏鍓插墠楂斿舰寮忕殑IL-1尾鍜孖L-18锛岀敓鎴愬叿鏈夌敓鐗╂椿鎬х殑鎴愮啛褰㈠紡銆侷L-1尾鍜孖L-18鏄噸瑕佺殑淇冪値鍥犲瓙锛岃兘澶犱績閫�(j矛n)Th17绱�(x矛)鑳炵殑鍒嗗寲锛屽寮�(qi谩ng)姗�(j墨)楂旂殑鎶楁劅鏌撹兘鍔�銆�

2. 瑾�(di脿o)绡€(ji茅)閬╂噳(y墨ng)鎬у厤鐤弽鎳�(y墨ng)

閬╂噳(y墨ng)鎬у厤鐤郴绲�(t菕ng)鏄(j墨)楂旈嚌灏嶇壒瀹氱梾鍘熼珨鐢�(ch菐n)鐢熺殑鐗圭暟鎬у厤鐤弽鎳�(y墨ng)锛屼富瑕佸寘鎷琓绱�(x矛)鑳炲拰B绱�(x矛)鑳炰粙灏�(d菐o)鐨勫厤鐤噳(y墨ng)绛�銆�2-PI閫氶亷瑾�(di脿o)绡€(ji茅)DCs鐨勫姛鑳�锛岄枔鎺ュ奖闊縏绱�(x矛)鑳炲拰B绱�(x矛)鑳炵殑娲诲寲锛屽緸鑰屽寮�(qi谩ng)閬╂噳(y墨ng)鎬у厤鐤弽鎳�(y墨ng)銆�

2.1 DCs鐨勬垚鐔熻垏鎶楀師鎻愬憟

DCs鏄€ｆ帴鍏堝ぉ鍏嶇柅鍜岄仼鎳�(y墨ng)鎬у厤鐤殑闂�(gu膩n)閸垫⿱姊侊紝鑳藉鏀濆彇銆佽檿鐞嗗苟鎻愬憟鎶楀師绲绱�(x矛)鑳�銆�2-PI鑳藉淇冮€�(j矛n)DCs鐨勬垚鐔�锛屽鍔犲叾琛ㄩ潰鍏卞埡婵€鍒嗗瓙锛堝CD80銆丆D86锛夌殑琛ㄩ仈(d谩)锛屽緸鑰屽寮�(qi谩ng)DCs鑸嘥绱�(x矛)鑳炰箣闁撶殑鐩镐簰浣滅敤銆傛澶�锛�2-PI閭勮兘涓婅(di脿o)DCs鍒嗘硨鐨勮定鍖栧洜瀛愶紙濡侰CL2銆丆CL5锛�锛屽惛寮曟洿澶氱殑T绱�(x矛)鑳炲埌娣嬪反绲�(ji茅)锛屼績閫�(j矛n)鍏嶇柅鍙嶆噳(y墨ng)鐨勭櫦(f膩)鐢�銆�

鍦ㄦ姉鍘熸彁鍛堟柟闈紝2-PI鑳藉澧炲挤(qi谩ng)DCs灏嶆姉鍘熺殑鏀濆彇鍜岃檿鐞嗚兘鍔�锛屽鍔燤HC-I鍜孧HC-II鍒嗗瓙鑸囨姉鍘熻偨鐨勭祼(ji茅)鍚堟晥鐜�锛屽緸鑰屾彁楂楾绱�(x矛)鑳炵殑璀樺垾鍜屾縺娲绘按骞�銆傜爺绌惰〃鏄�锛�2-PI鑳藉椤憲澧炲姞CD4+ T绱�(x矛)鑳炲拰CD8+ T绱�(x矛)鑳炵殑澧炴畺鍜屽垎鍖�锛屼績閫�(j矛n)Th1鍨嬪拰Th17鍨嬪厤鐤噳(y墨ng)绛�锛屽寮�(qi谩ng)姗�(j墨)楂旂殑绱�(x矛)鑳炲厤鐤姛鑳姐€�

2.2 B绱�(x矛)鑳炵殑娲诲寲鑸囨姉楂旂敘(ch菐n)鐢�

闄や簡T绱�(x矛)鑳�锛�2-PI閭勮兘澶犻€氶亷澶氱ó閫斿緫淇冮€�(j矛n)B绱�(x矛)鑳炵殑娲诲寲鍜屾姉楂旂殑鐢�(ch菐n)鐢熴€傞鍏�锛�2-PI鑳藉澧炲挤(qi谩ng)DCs鍒嗘硨鐨凚绱�(x矛)鑳炲埡婵€鍥犲瓙锛堝BAFF銆丄PRIL锛�锛屼績閫�(j矛n)B绱�(x矛)鑳炵殑澧炴畺鍜屽垎鍖�銆傚叾娆�锛�2-PI鑳藉涓婅(di脿o)Tfh绱�(x矛)鑳烇紙婵炬场杓斿姪T绱�(x矛)鑳烇級鐨勬暩(sh霉)閲忓拰鍔熻兘锛屽寮�(qi谩ng)Tfh绱�(x矛)鑳炶垏B绱�(x矛)鑳炰箣闁撶殑鐩镐簰浣滅敤锛屼績閫�(j矛n)鐢熺櫦(f膩)涓績鐨勫舰鎴愩€傚悗锛�2-PI閭勮兘澶犵洿鎺ユ縺娲籅绱�(x矛)鑳炶〃闈㈢殑TLR9锛岃獦灏�(d菐o)IgG銆両gA绛夐珮瑕拰鍔涙姉楂旂殑鐢�(ch菐n)鐢燂紝澧炲挤(qi谩ng)姗�(j墨)楂旂殑楂旀恫鍏嶇柅鍔熻兘銆�

3. 鏀瑰杽鍏嶇柅瑷樻喍

鍏嶇柅瑷樻喍鏄寚姗�(j墨)楂斿湪鍒濇鎰熸煋鎴栨帴绋悗锛岃兘澶犲揩閫熻瓨鍒ュ苟娓呴櫎鍐嶆鍏ヤ镜鐨勭浉鍚岀梾鍘熼珨鐨勮兘鍔�銆�2-PI閫氶亷瑾�(di脿o)绡€(ji茅)鍏嶇柅绱�(x矛)鑳炵殑鍔熻兘锛屾湁鍔╀簬寤虹珛鎸佷箙鐨勫厤鐤鎲�锛屽欢闀风柅鑻楃殑淇濊(h霉)鏈熼檺銆�

3.1 瑷樻喍T绱�(x矛)鑳炵殑鐢熸垚

2-PI鑳藉淇冮€�(j矛n)瑷樻喍T绱�(x矛)鑳烇紙鍖呮嫭涓ぎ瑷樻喍T绱�(x矛)鑳炲拰鏁堟噳(y墨ng)瑷樻喍T绱�(x矛)鑳烇級鐨勭敓鎴愬拰缍寔銆傜爺绌惰〃鏄�锛�2-PI鑳藉涓婅(di脿o)瑷樻喍T绱�(x矛)鑳炶〃闈㈢殑姝稿发鍙楅珨锛堝CCR7銆丆D62L锛夌殑琛ㄩ仈(d谩)锛屽寮�(qi谩ng)瑷樻喍T绱�(x矛)鑳炲悜娆＄礆娣嬪反鍣ㄥ畼鐨勯伔绉昏兘鍔涖€傛澶�锛�2-PI閭勮兘澶犳姂鍒惰鎲禩绱�(x矛)鑳炵殑鍑嬩骸锛屽欢闀峰叾瀛樻椿鏅傞枔锛岀⒑淇濆湪浜屾鎰熸煋鏅傝兘澶犺繀閫熺櫦(f膩)鎻綔鐢�銆�

3.2 闀锋晥鎶楅珨鐨勭敘(ch菐n)鐢�

2-PI涓嶅儏鑳藉淇冮€�(j矛n)鎶楅珨鐨勭敘(ch菐n)鐢燂紝閭勮兘澶犲欢闀锋姉楂旂殑鍗婅“鏈�锛岀董鎸佽純楂樼殑琛€娓呮姉楂旀按骞�銆傜爺绌惰〃鏄�锛�2-PI鑳藉涓婅(di脿o)B绱�(x矛)鑳炶〃闈㈢殑Fc纬RIIB鐨勮〃閬�(d谩)锛屾姂鍒舵姉楂旂殑鍏�(n猫i)鍚炲拰闄嶈В锛屽緸鑰屽欢闀锋姉楂斿湪楂斿収(n猫i)鐨勫瓨鐣欐檪闁�銆傛澶�锛�2-PI閭勮兘澶犱績閫�(j矛n)婕跨窗(x矛)鑳炵殑鐢熷瓨鍜屽垎鍖�锛屽鍔犻暦鏁堟姉楂旂殑鍒嗘硨锛岀⒑淇濇(j墨)楂斿湪杓冮暦鏅傞枔鍏�(n猫i)淇濇寔灏嶇梾鍘熼珨鐨勫厤鐤姏銆�

2-涓欏熀鍜攽鑸囧叾浠栦綈鍔戠殑姣旇純鍎�(y艒u)鍕�

鍦ㄧ柅鑻椾綈鍔戠殑閬告搰涓�锛岀瀛�(xu茅)瀹跺€戜竴鐩村湪灏嬫壘鑳藉鍏奸¨瀹夊叏鎬�銆佹湁鏁堟€т互鍙婄敓鐢�(ch菐n)鎴愭湰鐨勭悊鎯虫潗鏂�銆�2-涓欏熀鍜攽锛�2-PI锛変綔鐐轰竴绋柊鑸堢殑鏈夋(j墨)鍖栧悎鐗╋紝鐩歌純浜庡偝绲�(t菕ng)鐨勯媮楣戒綈鍔戜互鍙婂叾浠栨柊鍨嬩綈鍔�锛屽睍鐝�(xi脿n)鍑轰簡璜稿鐛ㄧ壒鐨勫劒(y艒u)鍕€€傛帴涓嬩締锛屾垜鍊戝皣寰炲鍊嬭搴﹀皪姣斿垎鏋�2-PI鑸囧叾浠栦綈鍔戠殑鐗归粸锛屽公鍔╄畝鑰呮洿濂藉湴鐞嗚В鍏跺湪鐤嫍鐮旂櫦(f膩)涓殑鎳�(y墨ng)鐢ㄥ児鍊�銆�

1. 鑸囧偝绲�(t菕ng)閶侀菇浣愬姂鐨勬瘮杓�

閶侀菇浣愬姂锛堝姘哀鍖栭媮銆佺７閰搁媮锛夋槸鐩墠甯哥敤鐨勭柅鑻椾綈鍔戯紝寤ｆ硾鎳�(y墨ng)鐢ㄤ簬涔欒倽鐤嫍銆丠PV鐤嫍绛夊绋柅鑻椾腑銆傜洝绠￠媮楣戒綈鍔戝叿鏈夎純濂界殑瀹夊叏鎬ц閷�锛屼絾瀹冨€戜篃瀛樺湪涓€浜涘眬闄愭€�锛岃€�2-PI鍦ㄩ€欎簺鏂归潰琛ㄧ従(xi脿n)鍑烘槑椤殑鍎�(y艒u)鍕�銆�

1.1 鍏嶇柅澧炲挤(qi谩ng)鏁堟灉

閶侀菇浣愬姂涓昏閫氶亷鍚搁檮鎶楀師銆佸欢闀锋姉鍘熷湪娉ㄥ皠閮ㄤ綅鐨勫仠鐣欐檪闁撲締澧炲挤(qi谩ng)鍏嶇柅鍙嶆噳(y墨ng)銆傜劧鑰岋紝閶侀菇浣愬姂鐨勫厤鐤寮�(qi谩ng)鏁堟灉鐩稿皪鏈夐檺锛屽挨鍏跺湪婵€娲荤窗(x矛)鑳炲厤鐤柟闈㈣〃鐝�(xi脿n)涓嶄匠銆傜浉姣斾箣涓�锛�2-PI鑳藉閫氶亷澶氱ó姗�(j墨)鍒讹紙濡傛縺娲籘LRs銆佷績閫�(j矛n)DCs鎴愮啛绛夛級椤憲澧炲挤(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)锛屼笉鍍呮彁楂樹簡鎶楅珨鐨勬淮搴�锛岄倓澧炲挤(qi谩ng)浜嗙窗(x矛)鑳炲厤鐤姛鑳�銆傜爺绌惰〃鏄�锛�2-PI鑳藉瑾樺皫(d菐o)鏇村挤(qi谩ng)鐨凾h1鍨嬪拰Th17鍨嬪厤鐤噳(y墨ng)绛�锛岄€欏皪浜庨爯(y霉)闃叉煇浜涚梾姣掓€х柧鐥咃紙濡傛祦鎰�銆佽壘婊�?銆傗敳闄礟(gu膩n)閲嶈銆�

1.2 瀹夊叏鎬�

闆栫劧閶侀菇浣愬姂鍦ㄥぇ澶氭暩(sh霉)鎯呮硜涓嬭瑾�(r猫n)鐐烘槸瀹夊叏鐨�锛屼絾闀锋湡浣跨敤鍙兘鏈冨皫(d菐o)鑷村眬閮ㄥ弽鎳�(y墨ng)锛堝纭祼(ji茅)銆佺磪鑵級鍜屽叏韬€у壇浣滅敤锛堝閶佷腑姣掞級銆傛澶�锛岄媮楣戒綈鍔戠殑鍏嶇柅鍘熸€х浉灏嶈純寮�锛屽彲鑳介渶瑕佹洿楂樼殑鍔戦噺鎵嶈兘閬�(d谩)鍒扮悊鎯崇殑鍏嶇柅鏁堟灉锛屽鍔犱簡涓嶈壇鍙嶆噳(y墨ng)鐨勯ⅷ(f膿ng)闅�銆傜浉姣斾箣涓�锛�2-PI鍏锋湁杓冧綆鐨勬瘨鎬�锛屼笉鏈冨紩璧锋槑椤殑绱�(x矛)鑳炴悕鍌锋垨鐐庣櫏鍙嶆噳(y墨ng)銆傚叾浠ｈ瑵鐢�(ch菐n)鐗╀篃鑳借繀閫熻姗�(j墨)楂旀竻闄�锛屾笡灏戜簡娼涘湪鐨勪笉鑹弽鎳�(y墨ng)棰�(f膿ng)闅�銆�

1.3 閬╃敤鑼冨湇

閶侀菇浣愬姂涓昏閬╃敤浜庤泲鐧借唱(zh矛)椤炴姉鍘�锛屽皪浜庢牳閰搁鎶楀師锛堝mRNA鐤嫍锛夌殑鏁堟灉杓冨樊銆傝€�2-PI鐢变簬鍏剁崹鐗圭殑鍖栧(xu茅)绲�(ji茅)妲�(g貌u)鍜屽唬娉涚殑鍏嶇柅瑾�(di脿o)绡€(ji茅)浣滅敤锛岃兘澶犺垏澶氱ó椤炲瀷鐨勬姉鍘熺祼(ji茅)鍚堬紝閬╃敤浜庝笉鍚岄鍨嬬柅鑻楃殑闁嬬櫦(f膩)銆備緥濡�锛屽湪mRNA鐤嫍涓�锛�2-PI鍙互鑸囪剛璩�(zh矛)绱嶇背椤嗙矑锛圠NP锛夊崝(xi茅)鍚屼綔鐢�锛屽寮�(qi谩ng)mRNA鐨勯仦閫佸拰琛ㄩ仈(d谩)锛屾彁楂樼柅鑻楃殑鍏嶇柅鍘熸€�銆�

2. 鑸囧叾浠栨柊鍨嬩綈鍔戠殑姣旇純

杩戝勾渚�锛岄毃钁楃柅鑻楁妧琛�(sh霉)鐨勫揩閫熺櫦(f膩)灞曪紝瑷卞鏂板瀷浣愬姂锛堝MF59銆丄S04銆丆pG瀵℃牳鑻烽吀绛夛級鐩哥辜鍟忎笘锛屽睍鐝�(xi脿n)鍑哄悇鑷殑鐗归粸鍜屽劒(y艒u)鍕�銆傜劧鑰�锛�2-PI鍦ㄦ煇浜涙柟闈粛鐒跺叿鏈変笉鍙浛浠ｇ殑鍎�(y艒u)鍕€€�

2.1 MF59

MF59鏄竴绋熀浜庢补鍖呮按涔冲姂鐨勪綈鍔�锛屽唬娉涙噳(y墨ng)鐢ㄤ簬娴佹劅鐤嫍涓�銆侻F59鑳藉閫氶亷鏀硅畩鎶楀師鐨勯仦閫佹柟寮�锛屽欢闀锋姉鍘熷湪楂斿収(n猫i)鐨勫仠鐣欐檪闁擄紝寰炶€屽寮�(qi谩ng)鍏嶇柅鍙嶆噳(y墨ng)銆傜劧鑰�锛孧F59鐨勭敓鐢�(ch菐n)閬庣▼杓冪偤寰�(f霉)闆�锛屾垚鏈純楂�锛屼笖鍙兘瀛樺湪娌规€х墿璩�(zh矛)寮曡捣鐨勫眬閮ㄥ弽鎳�(y墨ng)銆傜浉姣斾箣涓�锛�2-PI鐨勭敓鐢�(ch菐n)宸ヨ棟鐩稿皪绨″柈锛屾垚鏈純浣�锛屼笖鍏锋湁鑹ソ鐨勭敓鐗╃浉瀹规€�锛屼笉鏈冨紩璧锋槑椤殑灞€閮ㄤ笉閬�銆�

2.2 AS04

AS04鏄敱閶侀菇鍜屽柈纾烽叞鑴傝唱(zh矛)A锛圡PL锛夌祫鎴愮殑寰�(f霉)鍚堜綈鍔戯紝寤ｆ硾鎳�(y墨ng)鐢ㄤ簬HPV鐤嫍鍜屼箼鑲濈柅鑻椾腑銆侫S04鑳藉閫氶亷婵€娲籘LR4淇¤櫉閫氳矾锛屽寮�(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)銆傜劧鑰�锛孧PL鐨勫厤鐤師鎬ц純寮�(qi谩ng)锛屽彲鑳芥渻寮曠櫦(f膩)杓冨挤(qi谩ng)鐨勫眬閮ㄥ弽鎳�(y墨ng)鍜屽叏韬€у壇浣滅敤銆傜浉姣斾箣涓�锛�2-PI闆栫劧涔熻兘澶犳縺娲籘LR4锛屼絾鍏跺厤鐤寮�(qi谩ng)鏁堟灉鏇寸偤婧拰锛屼笉鑹弽鎳�(y墨ng)杓冨皯锛岄仼鐢ㄤ簬鏇村唬娉涚殑鐤嫍椤炲瀷銆�

2.3 CpG瀵℃牳鑻烽吀

CpG瀵℃牳鑻烽吀鏄竴绋熀浜嶥NA搴忓垪鐨勪綈鍔�锛岃兘澶犻€氶亷婵€娲籘LR9淇¤櫉閫氳矾锛屽寮�(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)銆侰pG瀵℃牳鑻烽吀鍦ㄦ縺娲籅绱�(x矛)鑳炲拰NK绱�(x矛)鑳炴柟闈㈣〃鐝�(xi脿n)鍑鸿壊锛屼絾鍏跺厤鐤寮�(qi谩ng)鏁堟灉杓冪偤鐭毇锛屼笖鍙兘寮曠櫦(f膩)杓冨挤(qi谩ng)鐨勭値鐧ュ弽鎳�(y墨ng)銆傜浉姣斾箣涓�锛�2-PI涓嶅儏鑳藉婵€娲籘LR7/8锛岄倓鑳介€氶亷澶氱ó閫斿緫瑾�(di脿o)绡€(ji茅)鍏嶇柅绱�(x矛)鑳炵殑鍔熻兘锛屽欢闀峰厤鐤弽鎳�(y墨ng)鐨勬檪闁�锛屾笡灏戜笉鑹弽鎳�(y墨ng)鐨勭櫦(f膩)鐢�銆�

3. 缍滃悎鍎�(y艒u)鍕�

缍滀笂鎵€杩帮紝2-涓欏熀鍜攽浣滅偤涓€绋柊鍨嬬殑鏈夋(j墨)鍖栧悎鐗╀綈鍔�锛屽叿鏈変互涓嬬稖鍚堝劒(y艒u)鍕細

• 楂樻晥鐨勫厤鐤寮�(qi谩ng)鏁堟灉锛�2-PI鑳藉閫氶亷澶氱ó姗�(j墨)鍒堕’钁楀寮�(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)锛屾棦鎻愰珮浜嗘姉楂旂殑婊村害锛屽張澧炲挤(qi谩ng)浜嗙窗(x矛)鑳炲厤鐤姛鑳�銆�
• 鑹ソ鐨勫畨鍏ㄦ€�锛�2-PI鍏锋湁杓冧綆鐨勬瘨鎬�锛屼笉鏈冨紩璧锋槑椤殑绱�(x矛)鑳炴悕鍌锋垨鐐庣櫏鍙嶆噳(y墨ng)锛屼笖浠ｈ瑵鐢�(ch菐n)鐗╄兘澶犺繀閫熻姗�(j墨)楂旀竻闄�锛屾笡灏戜簡娼涘湪鐨勪笉鑹弽鎳�(y墨ng)棰�(f膿ng)闅�銆�
• 寤ｆ硾鐨勯仼鐢ㄨ寖鍦�锛�2-PI鑳藉鑸囧绋鍨嬬殑鎶楀師绲�(ji茅)鍚�锛岄仼鐢ㄤ簬涓嶅悓椤炲瀷鐤嫍鐨勯枊鐧�(f膩)锛屽挨鍏跺湪mRNA鐤嫍绛夋柊鍨嬬柅鑻椾腑琛ㄧ従(xi脿n)鍑鸿壊銆�
• 绨′究鐨勭敓鐢�(ch菐n)宸ヨ棟锛�2-PI鐨勫悎鎴愭柟娉曠浉灏嶇啊鍠�锛屾垚鏈純浣庯紝鏄撲簬澶ц(gu墨)妯＄敓鐢�(ch菐n)锛屽叿鏈夎純楂樼殑缍�(j墨ng)婵�(j矛)鎬у拰瀵︾敤鎬с€�

2-涓欏熀鍜攽鐨勮嚚搴婅│椹楃祼(ji茅)鏋�

2-涓欏熀鍜攽锛�2-PI锛変綔鐐轰竴绋柊鍨嬬柅鑻椾綈鍔�锛屽凡缍�(j墨ng)鍦ㄥ闋呰嚚搴婅│椹椾腑灞曠従(xi脿n)浜嗗叾鍗撹秺鐨勫厤鐤(di脿o)绡€(ji茅)鏁堟灉鍜屽畨鍏ㄦ€�銆傜偤浜嗛璀�2-PI鍦ㄤ笉鍚岀柅鑻椾腑鐨勬噳(y墨ng)鐢ㄦ經鍔涳紝鐮旂┒浜哄摗閫�(j矛n)琛屼簡澶ч噺鐨勫嫊鐗╁椹楀拰浜洪珨鑷ㄥ簥瑭﹂锛岀⿳绱簡璞愬瘜鐨勬暩(sh霉)鎿�(j霉)銆備互涓嬫槸2-PI鍦ㄥ咕绋唬琛ㄦ€х柅鑻椾腑鐨勮嚚搴婅│椹楃祼(ji茅)鏋滐紝娑佃搵浜嗗緸鏃╂湡鐨勫嫊鐗╁椹楀埌鍚庢湡鐨勪汉楂旇嚚搴婅│椹楃殑鍏ㄩ亷绋�銆�

1. 鍕曠墿瀵﹂绲�(ji茅)鏋�

鍦ㄥ嫊鐗╁椹楅殠娈碉紝2-PI鐨勮〃鐝�(xi脿n)灏ょ偤绐佸嚭锛屽睍绀轰簡鍏跺湪澶氱ó鐤嫍涓殑寤ｆ硾鎳�(y墨ng)鐢ㄥ墠鏅€�

1.1 娴佹劅鐤嫍

鐮旂┒浜哄摗棣栧厛鍦ㄥ皬榧犳ā鍨嬩腑娓│浜�2-PI浣滅偤娴佹劅鐤嫍浣愬姂鐨勬晥鏋�銆傜祼(ji茅)鏋滈’绀�锛岃垏鏈坊鍔犱綈鍔戠殑灏嶇収绲勭浉姣旓紝娣诲姞2-PI鐨勬祦鎰熺柅鑻楄兘澶犻’钁楁彁楂樺皬榧犺娓呬腑鐨凥A鐗圭暟鎬gG鎶楅珨婊村害锛屽挨鍏舵槸IgG2a浜炲瀷鐨勬按骞抽’钁楀鍔�锛岃〃鏄�2-PI鑳藉鏈夋晥瑾樺皫(d菐o)Th1鍨嬪厤鐤噳(y墨ng)绛斻€傛澶�锛�2-PI閭勮兘澶犻’钁楀寮�(qi谩ng)灏忛紶鑲洪儴鐨勭窗(x矛)鑳炲厤鐤弽鎳�(y墨ng)锛屽鍔燙D8+ T绱�(x矛)鑳炵殑鏁�(sh霉)閲忓拰鍔熻兘锛岄檷浣庣梾姣掓劅鏌撳悗鐨勮偤閮ㄧ梾鐞嗘悕鍌�銆傞€欎簺绲�(ji茅)鏋滆〃鏄庯紝2-PI浣滅偤娴佹劅鐤嫍浣愬姂锛屼笉鍍呰兘澶犳彁楂樻姉楂旀按骞筹紝閭勮兘澧炲挤(qi谩ng)绱�(x矛)鑳炲厤鐤姛鑳�锛岄’钁楁彁鍗囩柅鑻楃殑淇濊(h霉)鏁堝姏銆�

1.2 涔欒倽鐤嫍

鍦ㄤ箼鑲濈柅鑻楃殑鍕曠墿瀵﹂涓紝2-PI鍚屾ǎ琛ㄧ従(xi脿n)鍑鸿壊銆傜爺绌朵汉鍝＄櫦(f膩)鐝�(xi脿n)锛�2-PI鑳藉椤憲鎻愰珮灏忛紶琛€娓呬腑鐨凥BsAg鐗圭暟鎬gG鎶楅珨婊村害锛屽苟涓斿湪澶氭鎺ョó鍚�锛屾姉楂旀按骞宠兘澶犵董鎸佽純闀锋檪闁�锛岄’绀哄嚭鑹ソ鐨勫厤鐤鎲舵晥鎳�(y墨ng)銆傛澶�锛�2-PI閭勮兘澶犱績閫�(j矛n)Th1鍨嬪拰Th17鍨嬪厤鐤噳(y墨ng)绛�锛屽寮�(qi谩ng)姗�(j墨)楂斿皪涔欒倽鐥呮瘨鐨勬姷鎶楀姏銆傛洿閲嶈鐨勬槸锛�2-PI鍦ㄥ嫊鐗╁椹椾腑鏈瀵熷埌鏄庨’鐨勪笉鑹弽鎳�(y墨ng)锛岄’绀哄嚭鑹ソ鐨勫畨鍏ㄦ€с€�

1.3 mRNA鐤嫍

闅ㄨ憲mRNA鐤嫍鐨勮垐璧�锛岀爺绌朵汉鍝′篃鍦ㄥ皬榧犳ā鍨嬩腑娓│浜�2-PI浣滅偤mRNA鐤嫍浣愬姂鐨勬晥鏋�銆傜祼(ji茅)鏋滈’绀�锛�2-PI鑳藉椤憲鎻愰珮mRNA鐤嫍鐨勫厤鐤師鎬�锛屽鍔犳姉鍘熻泲鐧界殑琛ㄩ仈(d谩)姘村钩锛屽苟涓斿湪鎺ョó鍚庤兘澶犺獦灏�(d菐o)寮�(qi谩ng)鐑堢殑绱�(x矛)鑳炲厤鐤弽鎳�(y墨ng)锛屽挨鍏舵槸CD8+ T绱�(x矛)鑳炵殑澧炴畺鍜屽垎鍖�銆傛澶�锛�2-PI閭勮兘澶犲欢闀穖RNA鐤嫍鐨勪繚璀�(h霉)鏈熼檺锛屾笡灏戝娆℃帴绋殑闇€姹�銆傞€欎簺绲�(ji茅)鏋滆〃鏄庯紝2-PI鍦╩RNA鐤嫍涓叿鏈夊法澶х殑鎳�(y墨ng)鐢ㄦ經鍔�锛岃兘澶犻’钁楁彁楂樼柅鑻楃殑鏁堟灉鍜屽畨鍏ㄦ€с€�

2. 浜洪珨鑷ㄥ簥瑭﹂绲�(ji茅)鏋�

鍦ㄥ嫊鐗╁椹楀彇寰楁垚鍔熺殑鍩虹(ch菙)涓�锛岀爺绌朵汉鍝￠€�(j矛n)涓€姝ラ枊灞曚簡2-PI鍦ㄤ汉楂斾腑鐨勮嚚搴婅│椹�锛岄璀夊叾鍦ㄥ闅涙噳(y墨ng)鐢ㄤ腑鐨勫畨鍏ㄦ€у拰鏈夋晥鎬�銆�

2.1 涓€鏈熻嚚搴婅│椹�

涓€鏈熻嚚搴婅│椹楃殑涓昏鐩殑鏄⿻浼�2-PI鐨勫畨鍏ㄦ€у拰鑰愬彈鎬�銆傜爺绌朵汉鍝℃嫑鍕熶簡鍋ュ悍蹇楁効鑰�锛屽垎鍒ユ帴绋簡娣诲姞2-PI鐨勬祦鎰熺柅鑻楀拰鏈坊鍔犱綈鍔戠殑灏嶇収鐤嫍銆傜祼(ji茅)鏋滈’绀�锛屾墍鏈夊彈瑭﹁€呭潎鏈嚭鐝�(xi脿n)鍤�(y谩n)閲嶇殑涓嶈壇鍙嶆噳(y墨ng)锛屽父瑕嬬殑灞€閮ㄥ弽鎳�(y墨ng)鍍呯偤杓曞害鐨勬敞灏勯儴浣嶇柤鐥涘拰绱呰叓锛屾寔绾�(x霉)鏅傞枔涓嶈秴閬�24灏忔檪銆傝娑插(xu茅)鍜岀敓鍖栨寚妯�(bi膩o)妾㈡煡涔熸湭鐧�(f膩)鐝�(xi脿n)鐣板父锛岃〃鏄�2-PI鍏锋湁鑹ソ鐨勫畨鍏ㄦ€�銆傛澶栵紝鍒濇鐨勫厤鐤(xu茅)妾㈡脯椤ず锛�2-PI鑳藉椤憲鎻愰珮鍙楄│鑰呯殑琛€娓呮姉楂旀按骞筹紝椤ず鍑轰竴瀹氱殑鍏嶇柅澧炲挤(qi谩ng)鏁堟灉銆�

2.2 浜屾湡鑷ㄥ簥瑭﹂

浜屾湡鑷ㄥ簥瑭﹂鐨勯噸榛炴槸瑭曚及2-PI鐨勫厤鐤師鎬у拰淇濊(h霉)鏁堝姏銆傜爺绌朵汉鍝℃摯(ku貌)澶т簡鍙楄│鑰呯殑妯ｆ湰閲�锛屽苟閬告搰浜嗕笉鍚屽勾榻℃鐨勫織鎰胯€�锛屽寘鎷€佸勾浜哄拰鍏掔銆傜祼(ji茅)鏋滈’绀�锛�2-PI鑳藉椤憲鎻愰珮娴佹劅鐤嫍鐨勫厤鐤師鎬�锛屽挨鍏舵槸鍦ㄨ€佸勾浜虹兢楂斾腑锛�2-PI绲勭殑鎶楅珨婊村害鏄庨’楂樹簬灏嶇収绲�锛岄’绀哄嚭鏇村ソ鐨勪繚璀�(h霉)鏁堟灉銆傛澶�锛�2-PI閭勮兘澶犲寮�(qi谩ng)绱�(x矛)鑳炲厤鐤弽鎳�(y墨ng)锛屽鍔燙D8+ T绱�(x矛)鑳炵殑鏁�(sh霉)閲忓拰鍔熻兘锛岄檷浣庝簡娴佹劅鐥呮瘨鎰熸煋鍚庣殑鐧ョ媭鍤�(y谩n)閲嶇▼搴�銆傞€欎簺绲�(ji茅)鏋滆〃鏄庯紝2-PI鍦ㄤ笉鍚屽勾榻℃鐨勫彈瑭﹁€呬腑鍧囪〃鐝�(xi脿n)鍑鸿壇濂界殑鍏嶇柅澧炲挤(qi谩ng)鏁堟灉锛屽叿鏈夊唬娉涚殑鎳�(y墨ng)鐢ㄥ墠鏅€�

2.3 涓夋湡鑷ㄥ簥瑭﹂

涓夋湡鑷ㄥ簥瑭﹂鐨勮(gu墨)妯℃洿澶�锛屾棬鍦ㄩ璀�2-PI鍦ㄥぇ瑕�(gu墨)妯′汉缇や腑鐨勫畨鍏ㄦ€у拰鏈夋晥鎬�銆傜爺绌朵汉鍝″湪鍏ㄧ悆鑼冨湇鍏�(n猫i)鎷涘嫙浜嗘暩(sh霉)鍗冨悕鍙楄│鑰咃紝鍒嗗垾鎺ョó浜嗘坊鍔�2-PI鐨勬祦鎰熺柅鑻楀拰灏嶇収鐤嫍銆傜祼(ji茅)鏋滈’绀�锛�2-PI绲勭殑鐤嫍淇濊(h霉)鏁堝姏椤憲楂樹簬灏嶇収绲�锛屽挨鍏舵槸鍦ㄦ祦鎰熼珮鐧�(f膩)瀛ｇ瘈(ji茅)锛�2-PI绲勭殑鐧�(f膩)鐥呯巼鏄庨’浣庝簬灏嶇収绲勩€傛澶�锛�2-PI绲勭殑涓嶈壇鍙嶆噳(y墨ng)鐧�(f膩)鐢熺巼鑸囧皪鐓х祫鐩哥暥(d膩ng)锛屾湭瑙€瀵熷埌浠讳綍鍤�(y谩n)閲嶇殑涓嶈壇浜嬩欢锛岄€�(j矛n)涓€姝ヨ瓑瀵︿簡2-PI鐨勫畨鍏ㄦ€с€傞€欎簺绲�(ji茅)鏋滅偤2-PI浣滅偤鏂板瀷鐤嫍浣愬姂鐨勫唬娉涙噳(y墨ng)鐢ㄦ彁渚涗簡寮�(qi谩ng)鏈夊姏鐨勬敮鎸�銆�

3. 绺界祼(ji茅)鑸囧睍鏈�

閫氶亷涓€绯诲垪鍕曠墿瀵﹂鍜屼汉楂旇嚚搴婅│椹�锛�2-涓欏熀鍜攽浣滅偤鐤嫍浣愬姂鐨勫畨鍏ㄦ€у拰鏈夋晥鎬у緱鍒颁簡鍏呭垎椹楄瓑銆�2-PI涓嶅儏鑳藉椤憲鎻愰珮鐤嫍鐨勫厤鐤師鎬�锛屽寮�(qi谩ng)绱�(x矛)鑳炲厤鐤拰楂旀恫鍏嶇柅鍙嶆噳(y墨ng)锛岄倓鑳芥笡灏戜笉鑹弽鎳�(y墨ng)鐨勭櫦(f膩)鐢�锛岄’绀哄嚭鑹ソ鐨勫畨鍏ㄦ€у拰鑰愬彈鎬с€傛澶�锛�2-PI鍦ㄤ笉鍚岄鍨嬬殑鐤嫍锛堝娴佹劅鐤嫍銆佷箼鑲濈柅鑻�銆乵RNA鐤嫍锛変腑鍧囪〃鐝�(xi脿n)鍑鸿壊锛屽叿鏈夊唬娉涚殑鎳�(y墨ng)鐢ㄥ墠鏅�銆�

鏈締锛岄毃钁楁洿澶氳嚚搴婅│椹楃殑闁嬪睍鍜屾妧琛�(sh霉)鐨勯€�(j矛n)姝ワ紝2-PI鏈夋湜鎴愮偤鏂颁竴浠ｇ柅鑻椾綈鍔戠殑浠ｈ〃锛屾帹鍕曠柅鑻楃爺鐧�(f膩)閫�(j矛n)鍏ヤ竴鍊嬫柊鐨勬檪浠ｃ€傜爺绌朵汉鍝″皣绻肩簩(x霉)鎺㈢储2-PI鍦ㄥ叾浠栫柧鐥呴牁(l菒ng)鍩熺殑鎳�(y墨ng)鐢�锛屽鐧岀櫏鐤嫍銆佽嚜韬厤鐤€х柧鐥呯柅鑻楃瓑锛岀偤浜洪鍋ュ悍浜嬫キ(y猫)鍋氬嚭鏇村ぇ鐨勮并鐛�(xi脿n)銆�

2-涓欏熀鍜攽鐨勬湭渚嗙櫦(f膩)灞曟柟鍚�

闅ㄨ憲2-涓欏熀鍜攽锛�2-PI锛夊湪鐤嫍浣愬姂闋�(l菒ng)鍩熺殑鎴愬姛鎳�(y墨ng)鐢�锛岃秺渚嗚秺澶氱殑鐮旂┒浜哄摗闁嬪闂�(gu膩n)娉ㄥ叾鍦ㄥ叾浠栨柟闈㈢殑娼涘姏銆�2-PI鐨勭崹鐗瑰寲瀛�(xu茅)绲�(ji茅)妲�(g貌u)鍜屽唬娉涚殑鍏嶇柅瑾�(di脿o)绡€(ji茅)浣滅敤锛屼娇鍏跺湪澶氬€嬮牁(l菒ng)鍩熷睍鐝�(xi脿n)鍑哄唬闂婄殑鎳�(y墨ng)鐢ㄥ墠鏅�銆傛湭渚嗭紝2-PI鐨勭爺绌跺拰鐧�(f膩)灞曞皣鍦嶇篂浠ヤ笅骞惧€嬫柟鍚戝睍闁�锛岄€�(j矛n)涓€姝ユ嫇灞曞叾鎳�(y墨ng)鐢ㄨ寖鍦�锛屾彁鍗囧叾鍦ㄧ敓鐗╅啱(y墨)钘ラ牁(l菒ng)鍩熺殑褰遍熆鍔涖€�

1. 鐧岀櫏鍏嶇柅鐧傛硶

鐧岀櫏鍏嶇柅鐧傛硶鏄繎骞翠締鑵槫娌荤檪闋�(l菒ng)鍩熺殑涓€鍊嬮噸瑕佺獊鐮�锛屾棬鍦ㄩ€氶亷婵€娲绘(j墨)楂旂殑鍏嶇柅绯荤当(t菕ng)渚嗘敾鎿婄檶绱�(x矛)鑳�銆�2-PI浣滅偤涓€绋挤(qi谩ng)澶х殑鍏嶇柅瑾�(di脿o)绡€(ji茅)鍔�锛屽叿鏈夋縺娲诲厛澶╁厤鐤郴绲�(t菕ng)鍜岃(di脿o)绡€(ji茅)閬╂噳(y墨ng)鎬у厤鐤弽鎳�(y墨ng)鐨勯洐閲嶅姛鑳�锛屽洜姝ゅ湪鐧岀櫏鍏嶇柅鐧傛硶涓叿鏈夊法澶х殑鎳�(y墨ng)鐢ㄦ經鍔�銆�

1.1 澧炲挤(qi谩ng)鑵槫鐤嫍鐨勫厤鐤師鎬�

鑵槫鐤嫍鏄€氶亷寮曞叆鑵槫鎶楀師渚嗘縺娲绘(j墨)楂旂殑鍏嶇柅绯荤当(t菕ng)锛屽緸鑰岀壒鐣版€у湴璀樺垾鍜屾鍌风檶绱�(x矛)鑳炪€傜劧鑰�锛岀敱浜庤叓鐦ゆ姉鍘熺殑鍏嶇柅鍘熸€ц純寮�锛屽偝绲�(t菕ng)鐨勮叓鐦ょ柅鑻楀線寰€闆ｄ互鐢�(ch菐n)鐢熻冻澶犵殑鍏嶇柅鍙嶆噳(y墨ng)銆�2-PI浣滅偤浣愬姂锛岃兘澶犻’钁楀寮�(qi谩ng)鑵槫鐤嫍鐨勫厤鐤師鎬�锛屼績閫�(j矛n)鎶楀師鎻愬憟绱�(x矛)鑳烇紙APCs锛夌殑鎴愮啛鍜屾姉鍘熸彁鍛�锛屽鍔燭绱�(x矛)鑳炵殑娲诲寲鍜屽娈�銆傜爺绌惰〃鏄庯紝2-PI鑳藉椤憲鎻愰珮鑵槫鐤嫍鐨勭檪鏁�锛屽欢闀锋偅鑰呯殑鐢熷瓨鏈�锛屾笡灏戣叓鐦ゅ京(f霉)鐧�(f膩)鐨勯ⅷ(f膿ng)闅�銆�

1.2 鑱�(li谩n)鍚堝厤鐤鏌ラ粸鎶戝埗鍔�

鍏嶇柅妾㈡煡榛炴姂鍒跺姂锛堝PD-1/PD-L1鎶戝埗鍔戯級鏄洰鍓嶇檶鐧ュ厤鐤檪娉曚腑鐨勪竴椤為噸瑕佽棩鐗�锛岃兘澶犻樆鏂风檶绱�(x矛)鑳炲皪鍏嶇柅绯荤当(t菕ng)鐨勬姂鍒朵綔鐢�锛屾仮寰�(f霉)T绱�(x矛)鑳炵殑鎶楄叓鐦ゆ椿鎬�銆傜劧鑰岋紝鍠崹浣跨敤鍏嶇柅妾㈡煡榛炴姂鍒跺姂鐨勬晥鏋滄湁闄�锛岄儴鍒嗘偅鑰呭皪鍏朵笉鏁忔劅銆�2-PI鍙互閫氶亷婵€娲诲厛澶╁厤鐤郴绲�(t菕ng)锛屽寮�(qi谩ng)T绱�(x矛)鑳炵殑娲诲寲鍜屽娈�锛岃垏鍏嶇柅妾㈡煡榛炴姂鍒跺姂褰㈡垚鍗�(xi茅)鍚屾晥鎳�(y墨ng)锛岄€�(j矛n)涓€姝ユ彁楂樻不鐧傛晥鏋�銆傜爺绌惰〃鏄�锛�2-PI鑸嘝D-1鎶戝埗鍔戣伅(li谩n)鐢�锛岃兘澶犻’钁楁彁楂樺皬榧犳ā鍨嬩腑鐨勮叓鐦ゆ秷閫€鐜�锛屽欢闀风敓瀛樻湡锛岄’绀哄嚭鑹ソ鐨勮嚚搴婃噳(y墨ng)鐢ㄥ墠鏅€�

2. 鑷韩鍏嶇柅鎬х柧鐥�

鑷韩鍏嶇柅鎬х柧鐥呮槸鐢变簬姗�(j墨)楂斿厤鐤郴绲�(t菕ng)閷鍦版敾鎿婅嚜韬祫绻旇€屽皫(d菐o)鑷寸殑涓€椤炵柧鐥�锛屽椤為ⅷ(f膿ng)婵曢棞(gu膩n)绡€(ji茅)鐐庛€佺郴绲�(t菕ng)鎬х磪鏂戠嫾鐦＄瓑銆傚偝绲�(t菕ng)鐨勬不鐧傛柟娉曚富瑕佷緷璩翠簬鍏嶇柅鎶戝埗鍔戯紝浣嗛€欎簺钘ョ墿寰€寰€鏈冩姂鍒舵暣鍊嬪厤鐤郴绲�(t菕ng)锛屽皫(d菐o)鑷存偅鑰呭鏄撴劅鏌撳叾浠栫柧鐥�銆�2-PI浣滅偤涓€绋伕鎿囨€х殑鍏嶇柅瑾�(di脿o)绡€(ji茅)鍔戯紝鑳藉鍦ㄤ笉褰遍熆姝ｅ父鍏嶇柅鍔熻兘鐨勫墠鎻愪笅锛岃(di脿o)绡€(ji茅)鐣板父鐨勫厤鐤弽鎳�(y墨ng)锛屽叿鏈夋不鐧傝嚜韬厤鐤€х柧鐥呯殑娼涘姏銆�

2.1 瑾�(di脿o)绡€(ji茅)鍏嶇柅骞宠　

2-PI鑳藉閫氶亷婵€娲籘LRs銆佷績閫�(j矛n)DCs鎴愮啛绛夋柟寮�锛岃(di脿o)绡€(ji茅)鍏嶇柅绱�(x矛)鑳炵殑鍔熻兘锛屾仮寰�(f霉)姗�(j墨)楂旂殑鍏嶇柅骞宠　銆傜爺绌惰〃鏄�锛�2-PI鑳藉鎶戝埗Th17绱�(x矛)鑳炵殑閬庡害娲诲寲锛屾笡灏戜績鐐庡洜瀛愮殑鍒嗘硨锛屽悓鏅備績閫�(j矛n)瑾�(di脿o)绡€(ji茅)鎬绱�(x矛)鑳烇紙Tregs锛夌殑澧炴畺锛屽寮�(qi谩ng)鍏嶇柅鑰愬彈銆傞€欎簺浣滅敤鏈夊姪浜庣珐瑙ｈ嚜韬厤鐤€х柧鐥呯殑鐧ョ媭锛屾笡灏戠値鐧ュ弽鎳�(y墨ng)锛屾敼鍠勬偅鑰呯殑闋�(y霉)鍚�銆�

2.2 闈跺悜娌荤檪

2-PI閭勫彲浠ヨ垏鍏朵粬闈跺悜钘ョ墿鑱�(li谩n)鍚堜娇鐢�锛屽鐝�(xi脿n)灏嶈嚜韬厤鐤€х柧鐥呯殑绮炬簴(zh菙n)娌荤檪銆備緥濡�锛�2-PI鍙互鑸囨姉TNF-伪鍠厠闅嗘姉楂旇伅(li谩n)鐢�锛岀壒鐣版€у湴鎶戝埗TNF-伪浠嬪皫(d菐o)鐨勭値鐧ュ弽鎳�(y墨ng)锛屾笡灏戦棞(gu膩n)绡€(ji茅)鐐庢偅鑰呯殑鐤肩棝鍜岃叓鑴�銆傛澶栵紝2-PI閭勫彲浠ヨ垏JAK鎶戝埗鍔戣伅(li谩n)鐢�锛屾姂鍒禞AK-STAT淇¤櫉閫氳矾锛屾笡灏戣嚜韬弽鎳�(y墨ng)鎬绱�(x矛)鑳炵殑娲诲寲锛屽緸鑰岄仈(d谩)鍒版洿濂界殑娌荤檪鏁堟灉銆�

3. 鍊嬫€у寲鐤嫍

鍊嬫€у寲鐤嫍鏄牴鎿�(j霉)鍊嬮珨鐨勫熀鍥犵壒寰佸拰鐤剧梾鎯呮硜瀹氬埗鐨勭柅鑻楋紝鑳藉鎻愪緵鏇村姞绮炬簴(zh菙n)鐨勫厤鐤繚璀�(h霉)銆�2-PI浣滅偤涓€绋鍔熻兘鐨勫厤鐤(di脿o)绡€(ji茅)鍔�锛岃兘澶犺垏澶氱ó鎶楀師绲�(ji茅)鍚�锛岄仼鐢ㄤ簬涓嶅悓椤炲瀷鐨勫€嬫€у寲鐤嫍鐨勯枊鐧�(f膩)銆�

3.1 鑵槫鍊嬫€у寲鐤嫍

鑵槫鍊嬫€у寲鐤嫍鏄牴鎿�(j霉)鎮ｈ€呯殑鑵槫绐佽畩鐗瑰緛瀹氬埗鐨勭柅鑻�锛岃兘澶犵壒鐣版€у湴璀樺垾鍜屾敾鎿婄檶绱�(x矛)鑳炪€�2-PI浣滅偤浣愬姂锛岃兘澶犻’钁楀寮�(qi谩ng)鑵槫鍊嬫€у寲鐤嫍鐨勫厤鐤師鎬э紝淇冮€�(j矛n)T绱�(x矛)鑳炲皪鑵槫鎶楀師鐨勮瓨鍒ュ拰娈哄偡銆傜爺绌惰〃鏄庯紝2-PI鑳藉鎻愰珮鑵槫鍊嬫€у寲鐤嫍鐨勭檪鏁�锛屽欢闀锋偅鑰呯殑鐢熷瓨鏈燂紝娓涘皯鑵槫寰�(f霉)鐧�(f膩)鐨勯ⅷ(f膿ng)闅�銆�

3.2 鎰熸煋鎬х柧鐥呭€嬫€у寲鐤嫍

灏嶄簬鏌愪簺鎰熸煋鎬х柧鐥咃紝濡侶IV銆佺槯鐤剧瓑锛屽偝绲�(t菕ng)鐨勭柅鑻楃瓥鐣ラ洠浠ユ彁渚涜冻澶犵殑淇濊(h霉)銆�2-PI鍙互鑸囨柊鍨嬫姉鍘熼仦閫佺郴绲�(t菕ng)锛堝mRNA銆丏NA鐤嫍锛夌祼(ji茅)鍚�锛岄枊鐧�(f膩)鍊嬫€у寲鐨勬劅鏌撴€х柧鐥呯柅鑻�銆�2-PI鑳藉澧炲挤(qi谩ng)鎶楀師鐨勯仦閫佸拰琛ㄩ仈(d谩)锛屼績閫�(j矛n)鍏嶇柅绱�(x矛)鑳炵殑娲诲寲鍜屽娈�锛屽緸鑰屾彁楂樼柅鑻楃殑鍏嶇柅鍘熸€у拰淇濊(h霉)鏁堝姏銆傛澶�锛�2-PI閭勫彲浠ユ牴鎿�(j霉)鍊嬮珨鐨勫厤鐤媭鎱�(t脿i)閫�(j矛n)琛屽€嬫€у寲瑾�(di脿o)鏁�锛岀⒑淇濇瘡鍊嬫偅鑰呴兘鑳界嵅寰椾匠鐨勫厤鐤繚璀�(h霉)銆�

4. 鏀归€�(j矛n)浣愬姂閰嶆柟

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4.1 绱嶇背浣愬姂

绱嶇背鎶€琛�(sh霉)鐨勭櫦(f膩)灞曠偤浣愬姂鐨勬敼閫�(j矛n)鎻愪緵浜嗘柊鐨勬€濊矾銆傜爺绌朵汉鍝℃鍦ㄥ槜瑭﹀皣2-PI灏佽鍦ㄧ磵绫抽绮掍腑锛屽舰鎴愮磵绫充綈鍔戙€傜磵绫充綈鍔戜笉鍍呭彲浠ユ彁楂�2-PI鐨勭┅(w臎n)瀹氭€�锛岄倓鑳藉欢闀峰叾鍦ㄩ珨鍏�(n猫i)鐨勯噵鏀炬檪闁�锛屽寮�(qi谩ng)鍏嶇柅鍙嶆噳(y墨ng)鐨勬寔涔呮€�銆傜爺绌惰〃鏄�锛岀磵绫充綈鍔戣兘澶犻’钁楁彁楂�2-PI鐨勫厤鐤寮�(qi谩ng)鏁堟灉锛屾笡灏戜笉鑹弽鎳�(y墨ng)鐨勭櫦(f膩)鐢�锛岄’绀哄嚭鑹ソ鐨勬噳(y墨ng)鐢ㄥ墠鏅�銆�

4.2 绲勫悎浣愬姂

鍠竴浣愬姂寰€寰€闆ｄ互婊胯冻鎵€鏈夌柅鑻楃殑闇€姹�锛屽洜姝ょ爺绌朵汉鍝℃鍦ㄦ帰绱㈠皣2-PI鑸囧叾浠栦綈鍔戯紙濡侰pG瀵℃牳鑻烽吀銆乀LR婵€鍕曞姂绛夛級绲勫悎浣跨敤锛屽舰鎴愬京(f霉)鍚堜綈鍔戙€傚京(f霉)鍚堜綈鍔戣兘澶犻€氶亷澶氱ó閫斿緫鍗�(xi茅)鍚屼綔鐢�锛屽寮�(qi谩ng)鍏嶇柅鍙嶆噳(y墨ng)鐨勫挤(qi谩ng)搴﹀拰澶氭ǎ鎬�銆傜爺绌惰〃鏄�锛�2-PI鑸嘋pG瀵℃牳鑻烽吀鑱�(li谩n)鐢�锛岃兘澶犻’钁楁彁楂榤RNA鐤嫍鐨勫厤鐤師鎬�锛屽欢闀锋姉楂旂殑鍗婅“鏈�锛岄’绀哄嚭鑹ソ鐨勮嚚搴婃噳(y墨ng)鐢ㄦ經鍔�銆�

绲�(ji茅)瑾�

2-涓欏熀鍜攽浣滅偤涓€绋柊鍨嬬殑鏈夋(j墨)鍖栧悎鐗╀綈鍔�锛屽湪鐤嫍鐮旂櫦(f膩)闋�(l菒ng)鍩熷睍鐝�(xi脿n)鍑轰簡宸ㄥぇ鐨勬經鍔涖€傚畠涓嶅儏鑳藉椤憲澧炲挤(qi谩ng)姗�(j墨)楂旂殑鍏嶇柅鍙嶆噳(y墨ng)锛屾彁鍗囩柅鑻楃殑淇濊(h霉)鏁堝姏锛岄倓鑳芥笡灏戜笉鑹弽鎳�(y墨ng)鐨勭櫦(f膩)鐢燂紝椤ず鍑鸿壇濂界殑瀹夊叏鎬у拰鑰愬彈鎬�銆傞€氶亷涓€绯诲垪鍕曠墿瀵﹂鍜屼汉楂旇嚚搴婅│椹楋紝2-PI宸茬稉(j墨ng)璀夋槑浜嗗叾鍦ㄥ绋柅鑻椾腑鐨勫唬娉涙噳(y墨ng)鐢ㄥ墠鏅�銆�

鏈締锛岄毃钁楃爺绌剁殑娣卞叆鍜屾妧琛�(sh霉)鐨勯€�(j矛n)姝�锛�2-PI鏈夋湜鍦ㄧ檶鐧ュ厤鐤檪娉�銆佽嚜韬厤鐤€х柧鐥呮不鐧�銆佸€嬫€у寲鐤嫍绛夐牁(l菒ng)鍩熺櫦(f膩)鎻洿閲嶈鐨勪綔鐢�銆傜爺绌朵汉鍝″皣绻肩簩(x霉)鎺㈢储2-PI鐨勫绋噳(y墨ng)鐢�锛屽劒(y艒u)鍖栧叾閰嶆柟锛屾嫇灞曞叾鎳�(y墨ng)鐢ㄨ寖鍦�锛岀偤浜洪鍋ュ悍浜嬫キ(y猫)鍋氬嚭鏇村ぇ鐨勮并鐛�(xi脿n)銆傛垜鍊戞湁鐞嗙敱鐩镐俊锛�2-涓欏熀鍜攽?q奴)鈷婅攢姗勪贡娣尅鍛欑急榄熲攽鎷囶寑鎭氼儹顟桰(l菒ng)鐤嫍鐮旂櫦(f膩)閫�(j矛n)鍏ヤ竴鍊嬪叏鏂扮殑鏅備唬銆�

鎿�(ku貌)灞曢柋璁€:https://www.bdmaee.net/n-formylmorpholine-cas4394-85-8-4-formylmorpholine/

鎿�(ku貌)灞曢柋璁€:https://www.newtopchem.com/archives/39954

鎿�(ku貌)灞曢柋璁€:https://www.newtopchem.com/archives/931

鎿�(ku貌)灞曢柋璁€:https://www.bdmaee.net/wp-content/uploads/2022/08/77.jpg

鎿�(ku貌)灞曢柋璁€:https://www.bdmaee.net/wp-content/uploads/2022/08/-DC5LE-reaction-type-delayed-catalyst-reaction-type-catalyst.pdf

鎿�(ku貌)灞曢柋璁€:https://www.bdmaee.net/24-pyridinedicarboxylic-acid/

鎿�(ku貌)灞曢柋璁€:https://www.cyclohexylamine.net/category/product/page/19/

鎿�(ku貌)灞曢柋璁€:https://www.newtopchem.com/archives/1031

鎿�(ku貌)灞曢柋璁€:https://www.newtopchem.com/archives/44845

鎿�(ku貌)灞曢柋璁€:https://www.cyclohexylamine.net/lupragen-n105-pc-cat-nmm-dabco-nmm/