異體造血幹細胞移植簡介 (Allogeneic hematopoietic stem cell transplantation) 李 啟 誠...
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Transcript of 異體造血幹細胞移植簡介 (Allogeneic hematopoietic stem cell transplantation) 李 啟 誠...
異體造血幹細胞移植簡介(Allogeneic hematopoietic stem
cell transplantation)
李 啟 誠 醫 師
E. DONNALL THOMAS, M.D.
Nobel Prize in Physiology or Medicine, 1990
for his pioneering work on bone marrow transplantation
造血幹細胞移植的歷史19571957: Thomas ED et.al.:
1st attempt of BMT in human beings (failure; HLA was identified in 1960+)
19591959: Thomas ED et.al.: 2nd attempt of BMT in identical twin
(hematological recovery occurred in 2 weeks, but
leukemia recurred months later)
Allogeneic HSCT, for What?
To replace incorrigible hematopoietic defectsTo replace incorrigible hematopoietic defects:• Quantitative defect: 再生不良性貧血 /Fanconi’s
anemia• Qualitative defect:
– 惡性疾病 : 各種急性或慢性, 骨髓性或淋巴球性白血病 ,淋巴癌 , 多發性骨髓瘤
– 非惡性疾病 :•骨髓造血幹細胞缺陷疾病 : 重度免疫不全症候•造血細胞基因缺損 : 嚴重型地中海型貧血•酵素相關基因缺陷 : 大理石症, 高雪氏症, 黏寶寶
造血幹細胞移植的種類
• 自體移植 (Autologous)
• 異體移植 (Allogeneic)
• 同卵雙胞胎移植 (Syngeneic)
異體移植 (Allogeneic Transplantation)
異體移植 : 捐贈者免疫基因須與病人相符
淋巴球
•MHC–Major HLA (MHC)
•Class I: A, B, C, E, H, G, F•Class II: DR, DQ, DP, DM, •Class III: not so important
–Minor HLA (mHC)•Non-MHC
–KIR–NOD
Resolution
• Low resolution– Serologically antigen (ex. A01)– CREG (cross-reactive groups)
• Intermediate resolution (ex. A0101/ 0102/ 0105)
• High resolution (ex. *A0101)
異體移植
• 親屬間異體移植 (sibling or other
family donors)
• 非親屬間異體移植 (unrelated donor;
MUD: HLA-matched unrelated donor)
造血幹細胞的來源
• 骨髓幹細胞 (Bone marrow; BMT)
• 週邊血液幹細胞 (Peripheral blood stem cell; PBSCT)
• 臍帶血幹細胞 (Cord blood stem cell; CBT)
異體造血幹細胞移植之步驟
正常骨髓
急性血癌
殲滅療法
死傷殆盡
造血幹細胞移植
FHCRC 大廳服務中心
Allogeneic HSCT
• Conditioning therapy ( 殲滅療法 ): 高劑量化學治療或放射治療
TBI + Cy: Total body irradiation + Cyclophosphamide
BuCy: Busulfan + Cyclophosphamide
• Stem cell transplantation: Day 0
Evaluate engraftment
Evaluate GVHD
Control infection
四個階段• Conditioning to engraftment: D-7 to D30
• Early stage after engraftment: D30-D100
• Late stage after engraftment: D100 – 1yr
• Chronic stage after engraftment: > 1yr
Chimera
Tests for chimerism
• Erythrocyte Ag (ABO, Rh, MN…)• Cytogenetics of metaphase for sex
chromosome• FISH• STR(microsatellite)/VNTR(minisatellite) of
nuclear cells—even lineage-specific STR analysis (after FACS with sorting)
西雅圖華盛頓大學
Three major complications after allo-HSCT
• Infection
• Acute GVHD
• Chronic GVHD
Immunosuppressant
GVHD (GVT)
Immunosuppressant
Infection: bacteria, fungus, virus
GVHD (GVT)
Dilemma post allogeneic HSCT
Life-threatening
Disease relapse
Infection complications after allogeneic HSCT
Day 0 Day 100
Bacterial
Fungal
HSV CMV
PCP
1 year (or more)
Day 0 Day 100 1 year (or more)
Day 30
Life-threatening infection
• Invasive fungal infection
• CMV infection
Aspergillus pneumonia
CMV pneumonia
CMV colitis: edema, congestion and multiple ulcers in the sigmoid colon
Inclusion body
To prevent aGVHD:↓conditioning intensity ↓cytokine storm
To prevent aGVHD: Suppress T T-depletionLater DLI
PB BM
CD34 cells 3-4X 1X
T-cells 10X 1X
GVHD Mechanism
Changing Concepts: GVHD Syndrome After AlloHCT
Day 0 50 100 180 1 y 2 y 3 y 5 y
Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GI liver, musculoskeletal, lungs, GU
- Classic acute - Late acute - Classic chronic - Chronic overlap
Activity Damage(inflammation) i n j u r y r e p a i r (fibrosis)
AlloreactivityAutoimmunity
Immunodeficiency
All I m
ages Ar e C
opy righ t Pro t ec t ed
Acute GVHD
• Engraftment to D+100• Alloreactive T-cells against HLA-bearing host tissue
• General performance decreased• Skin rash• Oral mucositis• Gastritis• Colitis• Hepatobiliary: hepatitis, jaundice• Cytopenia, thrombocytopenia• Impaired immunity
Skin GVHD
Severe oral GVHD: multiple ulcers
Chronic GVHD
• After D+100
• Appear as auto-immune phenomenon
• Sicca syndrome: dry eye, dry mouth
• Scleroderma
• Esophageal dysmotility
• Lung: obstructive lung disease (BO, BOOP)
• Hepatobiliary
• Cytopenia, thrombocytopenia
• Impaired immunity
Chronic GVHD of Skin: Day 170
InfectionsDisabilityQuality of lifeEndocrineMetabolismNutritionPain
Ocular sicca
Oral ulcers
Nail dystrophy
Skin sclerosis
Deep sclerosis
Bronchiolitis obliterans
Loss of bile ducts
Fasciitis
Skin ulcers
Spectrum of manifestations in chronic GVHD
All I m
a ge s Ar e C
op y ri gh t Pro t ec te d
Immunosuppressant
GVHD (GVT)
Immunosuppressant
Infection: bacteria, fungus, virus
GVHD (GVT)
Dilemma post allogeneic HSCT
Life-threatening
Disease relapse
Tulip
Patient evaluation toward medical staff
• Competence
• Courtesy
• Compassion
Neutral
Satisfied
Very satisfied
Thank You!