移植塊對宿主病

移植後嘅醫療併發症

移植塊對宿主病係一個症候羣,主要表現係嚮唔同嘅臟器有發炎,而呢個症候羣嚮接受咗骨髓或者造血幹細胞移植嘅病人入便好尋常。

移植塊對宿主病
同義詞GvHD
通常發病
  • 急性:移植完10-100日[1][2]
  • 慢性:移植完90-600日[3]
起因同種異體免疫
風險因數造血幹細胞移植
分類同拎
醫學專科emergency medicine
ICD-10T86.0
ICD-9-CM279.50
OMIM614395
DiseasesDB5388
MedlinePlus001309
eMedicine4290378867581050580
Orphanet39812

捐贈者免疫系統度啲白血球留咗嚮啲移植物嗰度,當個病人接受咗呢啲有捐贈者白血球嘅移植之後,呢啲白血球就會認為個宿主啲組織同細胞係外來嘢,係唔屬於自己嘅噉話,於是乎就去攻擊呢啲嘅宿主細胞同埋組織,因而導致咗呢個移植塊對宿主病。[4]佢好容易就同移植排斥混淆,但係移植排斥係調返轉,由個宿主啲白血球去對付返啲原本屬於啲捐贈者嘅細胞、組織或者器官。兩家嘅原理都係同種異體免疫,不過啲進程同細節有唔同。[5]

輸血有陣時都會引起移植塊對宿主病㗎,呢個時候我哋就嗌佢同輸血有挐褦嘅移植塊對宿主病,佢通常係因為啲血製品譬如紅血球、血漿或者血板仔冇經過gamma輻照或者白血球削減處理而導致嘅。同器官或者組織移植引起嘅移植塊對宿主病調返轉嚟,輸血引起嘅移植塊對宿主病係越匹配嘅人類白血球抗原就越容易引起呢個症候羣,尤其係直系或者近親之間嘅移植,千祈要因住。[4]

嚮2023年2月17號,即係情人節再過三日,世界移植塊對宿主病聯盟(一個非牟利組織)搞咗人類歷史上第一屆「移植塊對宿主病日」嚟到提高啲人對呢個病嘅認識同埋關注。喺呢一日,成千上萬嘅移植塊對宿主病嘅病人同埋親人嚮世界各地用自己嘅方法宣傳有關呢個病嘅嘢。[6][7]

類型 編輯

 
皮膚嘅移植塊對宿主病分級嘅顯微鏡圖像:從I級(表皮層最輕微嘅空泡化)到II級(空泡化同異形角質體形成),再到III級(下表皮裂隙形成),最後到IV級(真皮膚同表皮層分離) [8]

嚮臨牀設定,移植塊對宿主病分成急性同慢性,然後透過佢對唔同組織嘅影響同嚴重程度嚟分級。[9][10]

傳統嚟講,呢個急性嘅移植塊對宿主病係會用佢對啲特定嘅器官又或者組織嘅損壞嚟到分類嘅,譬如係對個, 皮膚 (引起皮疹), 粘膜同埋消化道嘅損壞。新近啲研究呢就發現移植塊對宿主病仲會對個免疫系統(或者造血系統骨髓 同埋甲狀腺)本身甚至個都會有影響。佢影響個肺嗰陣會造成呢個由免疫反應引起嘅肺炎。[11]一啲嘅生物標記可以用嚟認明移植塊對宿主病嘅源頭,譬如用 蛋白分解酵素抑制劑3 嚟認明呢個病嘅源頭嚮皮膚[12]

慢性嘅移植塊對宿主病同樣會攻擊上便提到嗰幾個器官,但係就因爲佢嘅長期效力,令到個移植塊對宿主病最後尾會影響埋啲 結締組織 同埋外分泌腺.[13]

急性同慢性嘅移植塊對宿主病對隻 嘅粘膜嘅破壞會導致嚴重嘅 同埋 𤶸, 從而會令性行為有困難。[14]

急性 編輯

急性嘅移植塊對宿主病通常嚮接受移植之後嘅第10日到第100日之間發病。[1][2]同時佢亦係爲咗降低移植嘅致殘同埋致死率嘅最大挑戰。[15]約莫有三成到五成嘅接受咗造血幹細胞移植嘅病人會出現急性嘅移植塊對宿主病。後生啲嘅病人又或者係人類白血球抗原配對較爲接近嘅病人就冇咁容易有急性嘅移植塊對宿主病。[16]

通常開初嘅症狀係手掌同腳底板皮膚出現皮疹、灼熱感同埋紅腫。呢一啲嘅症狀可能會蔓延到成個身都係。其他症狀包括心口悶、嘔、肚痛、肚屙(水咁稀兼且間唔中帶血)、冇胃口、黃疸、同埋體重減輕。

急性嘅消化道移植塊抗宿主病可能會導致嚴重嘅腸炎、黏膜甩落、嚴重嘅肚屙、肚痛、心口悶同埋嘔[17]。急性嘅消化道移植塊抗宿主病通常係透過腸道活檢嚟斷症。而個肝度嘅急性移植塊抗宿主病則係用啲急性病人嘅膽紅素水平嚟衡量[18]。對於皮膚度嘅急性嘅移植塊抗宿主病,佢會導致弥漫性紅色丘疹性皮疹[19],有時睇上去好似花邊噉樣。

急性嘅移植塊對宿主病係噉樣分級嘅:總體等級(皮膚-肝-腸),每個器官嘅分級係由I到IV級(1到4級)。有咗IV級嘅移植塊對宿主病嘅病人通常預後唔係幾好。如果移植塊對宿主病係好嚴重兼且需要用強烈嘅免疫抑制去醫,包括額外嘅類固醇同其他嘅用藥,噉個病人可能會因為免疫抑制而產生嚴重嘅感染[17],甚至乎畀啲感染害死。但係,一個嚮2016年嘅研究發現,近年嚟IV級移植塊對宿主病人嘅預後有所改善。[20]

慢性 編輯

移植後90日到600日之內通常會發生慢性嘅移植塊對宿主病。中ting2到嚴重嘅慢性移植塊對宿主病症狀會對啲病人嘅長期生存產生頗爲之負面嘅影響[21]

慢性移植塊對宿主病嘅開初症狀通常係手板或者腳底板啲皮膚發紅,同埋啲皮疹會擴散,同時啲皮膚通常係又痕又乾嘅。嚮啲嚴重病例入便,皮膚可能起泡同埋甩落,就好似嚴重曬傷咗噉樣。可能仲會發燒添。慢性移植塊對宿主病嘅其他症狀仲包括埋以下依啲:

  • 冇胃口
  • 肚痾
  • 肚痛
  • 體重變輕
  • 皮膚同隻眼發黄(黄疸)
  • 肝大
  • 肚脹
  • 位於右上方嘅肚痛
  • 血入便肝嘅酵素水平升高(驗血嗰陣顯示)
  • 感覺皮膚收得好緊
  • 隻眼又乾又揦住痕
  • 口乾或者潰瘍
  • 食酸嘢嗰陣感到揦住痛
  • 細菌感染
  • 肺嘅氣道仔阻塞

對於個口腔,慢性移植塊對宿主病嘅主要表現係生扁平苔蘚,兼呄比經典嗰啲口腔扁平苔蘚更之爲容易發生惡性轉化,變成口腔鱗狀細胞癌[22]相比之下,同移植塊對宿主病有挐褦嘅口腔癌可能有更加勁嘅殺傷力同埋啲病人嘅預後會差啲,呢個係同啲唔係造血幹細胞移植嘅病人嘅口腔癌嚟比。

病因 編輯

 
慢性移植塊抗宿主病嘅病理(三部曲:病人組織正常更替釋放抗原、捐贈者啲T細胞被激活、目標細胞畀捐贈者啲T細胞消滅)

移植塊對宿主病要發生嘅話必須滿足下便三個準則,即Billingham準則:[23]

  • 病人接受咗個捐贈者啲有活躍免疫細胞嘅移植塊。
  • 捐贈者同個病人啲組織兩家唔兼容。
  • 個病人有免疫缺陷,因此無辦法摧毀或者令到啲移植嘅活躍淋巴細胞失活。[24]

嚮個病人接受咗骨髓移植之後,移植塊入便嗰啲T細胞(唔理佢哋係污染物又好,又抑或係專登引入嘅都好) 會認為個宿主啲組織係外來嘢,因而去攻擊呢啲移植接受者嘅組織。T細胞會放出過晒量嘅細胞介素,包括TNF-α同干擾素γ(IFNγ)。好多宿主嘅抗原都可以引發移植塊抗宿主病,當中包括咗人類白血球抗原(HLA)。但即使係有HLA完全相同嘅兄弟姊妹作為捐贈者,移植塊抗宿主病都係有可能發生嘅。[25] HLA完全相同嘅兄弟姊妹或者啲冇血緣關係但HLA完全相同嘅捐贈者,佢哋通常會有唔同嘅基因蛋白(嗌做次要組織相容性抗原),呢一啲抗原可以由主要組織相容性複合體分子呈現畀捐贈者啲T細胞,而T細胞認為呢啲抗原係外來嘢,然之後就發生免疫反應。[26]

嚮接受咗移植之後嘅前便六個月,引起移植塊對宿主病嘅抗原主要係HLA-DR ,而對於前便兩年則係 HLA-B ,至於長期生還,就同 HLA-A 有挐褦。[27]

雖然啲捐贈者嘅T細胞並唔係我哋想要嘅,因為畢竟佢哋係引起移植塊對宿主病嘅罪魁禍首。之不過,呢啲捐贈者嘅T細胞都並唔係一無是處嘅,佢哋對移植塊嘅植入成功有好大嘅幫助,因為佢哋避免咗個病人嚮電療或者化療之後仍然殘留嘅免疫系統對個移植塊實行攻擊,從而導致移植塊排斥噉話。仲有呢就係造血幹細胞移植通常係用嚟醫癌嘅,當中呢又主要係嚟醫白血病,因此啲捐贈者嘅T細胞發揮著移植塊對腫瘤效用[28]一啲新近嘅同造血幹細胞移植有挐褦嘅研究就試圖將啲移植塊嘅對腫瘤效力同埋佢哋嘅對宿主組織嘅攻擊區分開嚟。[29]

機理 編輯

根據病理生理學,移植塊對宿主病嘅發生分成下便三個階段:[30]

  1. 傳入期:抗原呈獻細胞畀個宿主啲抗原激活
  2. 傳出期:T細胞被激活,然之後複製、分化同埋移動到去啲宿主嘅組織度
  3. 作用期:啲宿主嘅組織畀T細胞破壞

抗原呈獻細胞嘅激活係嚮第一階段發生嘅。嚮造血幹細胞移植之前,個病人亦即係即將接受移植嗰個宿主會先接受放療或者化療,呢啲噉樣嘅療法係愛嚟清走晒身體入邊啲癌細胞同埋啲壞嘅幹細胞。當然個宿主自己啲正常組織都會畀啲咁具有侵徹性嘅療法損害到,尤其係個腸粘膜,從而令啲微生物可以入到啲組織度,兼且刺激啲促炎細胞因子譬如IL-1同埋TNF-α嘅產生。呢啲促炎細胞因子增加咗抗原呈獻細胞上便啲主要組織相容性複合體分子同埋粘附分子嘅表達,從而提高咗抗原呈獻細胞呈獻抗原嘅能力。[31]

第二階段嘅主要特徵係效應細胞嘅活化。捐贈者啲T細胞嘅激活進一步增強咗主要組織相容性複合體分子同粘附分子、趨化因子、仲有CD8 +、CD4 + T細胞同埋啲來賓B細胞嘅擴增。喺最後階段,呢啲效應細胞移行到去目標器官度,造成組織損傷,甚至導致多個臟器衰竭。[32]

預防 編輯

  • 基於DNA嘅組織型鑑定會提供更為之準確嘅捐贈者同移植病人嘅人類白血球抗原配對,而有研究就證實咗呢一啲較為之準確嘅配對會好大程度噉降低移植塊對宿主病嘅發生概率同埋嚴重程度,從而提高啲病人嘅長期存活率。[33]
  • 臍帶血入便啲T細胞有著先天嘅免疫唔成熟,[34]因而用臍帶血入便啲造血幹細胞嚟做非親緣嘅移植嘅話,個移植塊對宿主病嘅發病概率同埋嚴重性都會有所降低。[35]
  • Methotrexate, cyclosporin 同埋tacrolimus 呢三種藥係用嚟預防移植塊對宿主病嘅常用藥。[36]另外我哋需要做更多嘅研究睇下啲人類間質細胞係咪真係可以用嚟預防到啲移植塊對宿主病。[37]
  • 透過一啲技術手段可以耗盡啲移植塊入便嘅T細胞,而噉樣做的而且確可以好大程度噉避免咗移植塊對宿主病。之不過,呢一啲耗盡咗T細胞嘅移植係以移植塊嘅抗腫瘤效應減弱、植入失敗或者癌症復發風險增加為代價嘅。[38]仲有呢就係呢啲嘅冇咗T細胞嘅移植會令到嘅病人免疫力唔夠,從而更加容易噉受到細菌、病毒同埋真菌嘅感染。一個多中心嘅研究表明,三年冇病嘅生存率同係咪移除咗啲T細胞冇挐褦。[39]


醫法 編輯

靜脈輸注類固醇,譬如prednisone,係急性移植塊對宿主病[40]同埋慢性移植塊對宿主病嘅標準醫法。[41]用呢啲類固醇嘅目的係壓制啲T細胞介導嘅針對啲宿主組織嘅免疫攻擊。但係,嚮高劑量嗰陣,呢一啲嘅免疫抑制增加咗感染同埋癌症復發嘅風險,所以要因住嚟用藥。因為噉,將移植之後高劑量類固醇嘅劑量減到較為之低嘅水平係啱嘅。嚮呢個時期,輕度嘅移植塊對宿主病係可以接受嘅,尤其係對於啲HLA唔匹配嘅病人嚟講,因為佢通常同個移植塊嘅對腫瘤效應有挐褦。[42]

環孢素同Tacrolimus都係鈣調磷酸酵素嘅抑製劑。呢啲藥雖然喺結構上唔同,但係就作用機制相同。環孢素同細胞質蛋白肽基脲酰基順反異構酵素A結合(嗌做環磷酰酵素),而Tacrolimus就同細胞質蛋白肽基脲酰基順反異構酵素FKBP12結合。呢啲結合物抑製啲鈣調磷酸酵素,令到啲激活咗嘅T細胞轉錄因子NFAT冇辦法去磷酸化同埋唔准佢入去個細胞核度。[43] 標準嘅預防醫法包括咗嚮六個月之內用環孢素同埋methotrexate,而環孢素嘅濃度應維持嚮200納克/毫升以上。[44]

其他經已被研究用嚟醫移植塊抗宿主病嘅藥包括:sirolimuspentostatinetanercept,同埋 alemtuzumab[45] 嚮2017年8月,美國嘢食同藥規管署(FDA)批准咗用ibrutinib嚟醫嗰啲試過一個或者以上嘅系統療程但係就失敗嘅慢性移植塊抗宿主病。[46]


臨牀研究 編輯

針對移植塊抗宿主病嘅醫法同埋預防嘅臨床試驗係有好多嘅,呢一啲嘅研究有啲就經已完咗,有啲呢就仲嚮度進行緊。 [47]

2012 年 5 月 17 號,Osiris Therapeutics醫藥公司宣布加拿大衛生監管機構批准咗Prochymal依隻新藥,呢隻係專門用嚟醫嗰啲類固醇醫唔到嘅細路哥啲急性移植塊抗宿主病嘅藥。 Prochymal係第一個畀監管機構批准用嚟醫系統病嘅干細胞類藥。 [48]

2016 年 1 月,Mesoblast 公佈咗對241個得咗急性移植塊抗宿主病嘅細路哥所做嘅2期臨床試驗結果,呢啲細路哥對類固醇冇反應。[49]呢個試驗用嘅係一種嗌做remestemcel-L或者MSC-100-IV 嘅間充乾細胞療法。 1個月之後病情有一定改善嘅病人嘅存活率係82%(對照組為係39%),而1 個月之後幾乎冇乜效果嘅病人嘅長期存活率係72%(對照組係18%)。[49]

清除愛滋 編輯

有啲愛滋病毒嘅攜帶人士就嚮接受咗醫癌嘅造血幹細胞移植之後得咗移植塊對宿主病,之後啲愛滋病毒就消失咗。呢啲罕見嘅例子包括咗有名嘅柏林病人同埋另外六個西班牙病人。[50]

睇埋 編輯

編輯

參攷 編輯

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