January 29, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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


High Th1 and Th2 Th1/Th2=1/1 (means higher Th2) Higher DC2


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: – – –

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 • • • • •

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


Tests for chimerism • • • •

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)





Need diuretic, analgesia, finally complete resolution

MOF, esp renal, lung, CNS









D+100 mortality




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 • • • • •

Urso Hepatic glutathione Steroid Heparin is ineffective/dangerous Defibrotide

Pulmonary Function Test

Vaccination •

活菌: – – – – – – –

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: – – – – – – – – – – – – –

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)

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