Transcript Transplantation

Transplantation
Th1 and cytotoxic T-cell
Th2 and B-cell, allo-antibody
Dendritic cells and T-cells
• DC were gated as negative for specific
lineage markers (CD3, CD11b, CD14,
CD16, CD56, CD19, CD20, CD34) and
positive for HLA-DR.
• The DC1 and DC2 subsets were defined
as CD11c and CDw123 positive,
respectively
• DC1 Th1 CD8 T-cell cellular immunity
intracellular pathogen
• DC2 Th2 B-cell humeral immunity
extracellular pathogen
PB
BM
High Th1 and Th2
Th1/Th2=1/1
(means higher Th2)
Higher DC2
Th1/Th2=10/1
Isoforms of CD45
Immune Reconstruction
• Neutrophil and monocyte recovered fastest, and monocyte can work as
APC
• Immune recovery of lymphocyte function
– NK is the fastest among lymphocytes (Because NK developed in BM, not in
thymus)
– NK> CD8> CD4~B-cell
– More T-cell, recover faster, so, T-repleted PB> BM> T-cell depleted> Cord
blood (Ref. T-cell content: PB:10X, BM:X, CB:0.1X; partial TCD is 1.5~2.0 log;
rigorous TCD is 3.0~5.0 log)
– GVHD will slowdown immune recovery
– Young pts recovered faster than old
– ATG delayed T-cell immune reconstruction
• Humeral function recover
– 2-6m, IgM
– 9-12m, IgG1 and IgG3
– Years, IgG2, IgG4 and IgA
Match
• MHC, on chromosome 6p
– Major HLA (MHC)
• Class II: DP, DM, DQ, DR
• Class III: not so important
• Class I: B, C, E, A, H, G, F
– Minor HLA (mHC)
• Non-MHC
– KIR
– NOD
Resolution
• Low resolution
– Serlogically antigen
– CREG (crossreactive groups)
• Intermediate resolution
• High resolution
Vector of Mismatch
• HVG direction
• GVH direction
Conditioning Regimens
• Myeloablative
– TBI-based
• TBI-Cy
– Non-TBI based
• BuCy
• BEAM/ BEAC
• HD melphalan
• Non-myeloablative
Immunosuppressive Agents
• Nonspecific agents
– Steroid
• aGVHD, 2mg/kg/day for 2 wks, then taper, speed: 10% every 1 wks
• cHVGD, 1mg/kg/day for 2 wks, then taper
– MTX
• Standard dose: 15mg/m2 loading on D1, then 10mg/m2 on D3, 6, 11
• Mini dose: 5mg/m2 loading on D1, then 5mg/m2 on D3, 6, 11
Immunosuppressive Agents
• Specific T-cell immunosuppressive agents
– CsA
• Check CsA level QW1/W5, target level=200±50
• Shift to oral CsA around D+14 ~D+21 if fair oral intake (劑量約2倍)
• CsA duration:
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For standard pts: start to taper after D+56, DC around D+180
For high risk with post-SCT CR pts: start to taper after D+35, DC around D+90~D+120
For high risk with post-SCT persistent blasts pts:
» With GVHD: depends, keep minimal dose
» Without GVHD: taper ASAP even within 1 wk
For benign dz: may prolong CsA duration to 1 yr
• S/E:
– Cre, Bil, HUS/TTP
– Hypertension, hyperglycemia, headache, hirsutism
– Tacrolimus
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0.03mg/Kg/day. Check Tacrolimus level QW1/W5, target level=15±5
Shift to oral Tacrolimus around D+14 ~D+21 if fair oral intake (空腹吃, 劑量約2-3倍)
Effect: aGVHD decreased (compared with CsA), but most Grade 2
cGVHD is similar, but less extensive
Adverse events: less OS? Not sure!
Immunosuppressive Agents
– Sirolimus
– Mycophenolate mofetil (MMF)
• Effective in preventing HVG and GVH direction
• Dose: as high as 15mg/kg bid is tolerated
• Selective lymphocyte toxicity, sparing neutrophil
– Antibodies (Anti-CD3, IVIG, IVG)
• Others
– Thalidomide
• Used for cGVHD
– Clofazimine
– Hydroxychloroqine
Purging
• Positive purging
– CD34 selection with CliniMACS (magnetic beads)
• Negative purging
– In vitro Malfosfamide or 4-HC
(hydroperoxycyclophosphamide)
– In vivo Rituximab
Chimera
Tests for chimerism
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Erythrocyte Ag (ABO, Rh, MN…)
Cytogenetics of metaphase
FISH
STR(microsatellite)/VNTR(minisatellite) of
nuclear cells—even lineage-specific STR
analysis (after FACS with sorting)
VOD/
SOS (Sinusoidal obstruction syndrome)
• Typically onset before D+30
• Incidence: 10~60%
• In zone 3, subendothelial edema, hepatic venules thrombosis,
fibrosis, necrosis
 zone 3 has high level of CYP450 and glutathione-Stransferase activity
• Risk factors:
– TBI, Busulfan (probably due to drug absorption is variable, Busulfex is
less)
– Anti-CD33 (Mylotarg)
VOD/
SOS (Sinusoidal obstruction syndrome)
• Lab:
– PAI-1 (plasminogen activator inhibitor) increased,
usually>120 ng/mL (sensitivity 100%, specificity 30%)
– Usually profound thrombocytopenia, poor response to
transfusion
– Transvenous liver biopsy and wedged hepatic venous
pressure gradient measurement (WHVPG) is gold standard.
• WHVPG>10mm-Hg, sensitivity 52%, specificity 91%,
Diagnosis of VOD and Severity
Baltimore criteria
Seattle criteria
By D+21
Hyperbilirubinemia> 2mg/dL
By D+20
2 or more of:
Plus at least 2 of:
1.Painful hepatomegaly
2.Fluid retention or ascites
3.Suddon weight gain (>5% of baseline)
1.Hyperbilirubinemia >2mg/dL
2.Painful hepatomegaly
3.Unexplained weight gain (> 2% of
baseline)
Mild
Moderate
Severe
Self-limited
Need diuretic, analgesia, finally
complete resolution
MOF, esp renal, lung,
CNS
Bil
~4.7
~8
~26
Ascites
5%
16%
48%
D+100
mortality
3%
20%
98%
Prognosis predictor
• PAI-1
• Bil
Treatment of VOD
• Defibrotide
– polydeoxyribonucleotide with thrombolytic and
antithrombotic properties and no systemic anticoagulant
effect
– 25~60mg/kg/day, ivf 2 hrs, Q6H
– CR rate~50%
• Steroid?
• Anti-coagulant or thrombolytic agents
– t-PA/Heparin is contraindicated in VOD with MOF 
bleeding risk
Prevention of VOD
• RIST has less VOD
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Urso
Hepatic glutathione
Steroid
Heparin is ineffective/dangerous
Defibrotide
Pulmonary Function Test
Vaccination
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活菌:
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卡介苗(BCG)
麻疹(Measles)
腮腺炎(Mumps)
口服型小兒麻痺(Poliomyelitis, 沙賓口服疫苗Sabin)
德國麻疹(Rubella)
水痘(Varicella)
黃熱病(Yellow fever)
死菌:
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霍亂(Cholera)
百日咳(Pertussis)
鼠疫(黑死病,plaque)
肺炎雙球菌(Pneumococcus)
副傷寒(Typyoid)
b型流行性感冒嗜血桿菌(Haemophilus influenzae type b, Hib
B型肝炎疫苗(Hepatitis B)
流行性感冒(Influenza)
注射型小兒麻痺疫苗(Poliomyelitis, 沙克注射疫苗Salk)
狂犬病(Rabies)
白喉(Diphtheria)
破傷風(Tetanus)
炭疽病(Anthrax)