Transplantation

1. Transplantation

3. Th1 and cytotoxic T-cell

4. Th2 and B-cell, allo-antibody

5. 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

6. DC1 Th1 CD8 T-cell cellular immunity intracellular pathogen • DC2 Th2 B-cell humeral immunity extracellular pathogen

7. Isoforms of CD45

8. 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

10. 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

11. Resolution • Low resolution • Serlogically antigen • CREG (crossreactive groups) • Intermediate resolution • High resolution

12. Vector of Mismatch • HVG direction • GVH direction

13. Conditioning Regimens • Myeloablative • TBI-based • TBI-Cy • Non-TBI based • BuCy • BEAM/ BEAC • HD melphalan • Non-myeloablative

14. 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

15. 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!

16. 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

18. Purging • Positive purging • CD34 selection with CliniMACS (magnetic beads) • Negative purging • In vitro Malfosfamide or 4-HC (hydroperoxycyclophosphamide) • In vivo Rituximab

20. Chimera

21. 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)

25. 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-S-transferase activity • Risk factors: • TBI, Busulfan (probably due to drug absorption is variable, Busulfex is less) • Anti-CD33 (Mylotarg)

26. 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, sensitivity52%, specificity 91%,

27. Diagnosis of VOD and Severity

28. Prognosis predictor • PAI-1 • Bil

29. 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

30. Prevention of VOD • RISThas less VOD • Urso • Hepatic glutathione • Steroid • Heparin is ineffective/dangerous • Defibrotide

31. Pulmonary Function Test

35. 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)