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)

Th1/Th2=10/1

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

Chimera

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-S-

transferase 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 SeverityBaltimore criteria Seattle criteria

By D+21 Hyperbilirubinemia> 2mg/dL

Plus at least 2 of:1.Painful hepatomegaly2.Fluid retention or ascites3.Suddon weight gain (>5% of baseline)

By D+202 or more of:

1.Hyperbilirubinemia >2mg/dL2.Painful hepatomegaly3.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

• 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)