Tolerance Induction

1
Tolerance Induction

• Dr. S. Strober
• Stanford University

2
Holy Grails

• Graft Anti- Tumor Activity without Graft vs Host
  Disease after Bone Marrow Transplantation for
  Leukemia/Lymphoma
• Organ Transplant Acceptance without Mainteneance
  Immunosuppressive Drugs(Immune Tolerance)

3
Total Lymphoid Irradiation

• Treatment for Hodgkins Disease
• Safe and effective (10,000 patients )
• Multiple small doses of irradiation
• Targeted to lymph nodes, spleen , and
  thymus-other tissues shielded
• Outpatient procedure

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Non-Myeloablative TLI/ATS Protocol
Donor C57BL/6 (H2b) Bone marrow or - Spleen
or blood T cells
Total Lymphoid Irradiation17 Doses (240 cGy/dose)
Recipient BALB/c
D-24 D-12 D-10 D-8
D-1 D0
ATS i.p. Injections
Figure by A. Pillai MD
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TLI ATG Treated Mice are Resistant to GVHD
Lan F. et al., J. Immunol. 167, 2001
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TLI/ATG Conditioning for Hematolymphoid
Malignancies Using MRD/URD
GVHD prophylaxis
ATG 1.5 mg/kg/day
CSA
Day 0
Days -11 to -7
MMF
Day 180
Days -4 to -1
Days -11 to -7
Infection Prophylaxis HSV if ve acyclovir 400
mg BID CMV blood PCR weekly EBV blood PCR every
2 weeks PCP Septra DS BID weekends D42 Fungus
if prior infection or URD
TLI 800 cGy over 10 fractions
Lowsky R, et al., NEJM Sept 2005
7
Sykes and Spitzer, Nat. Med.11,1164 2005
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Non-Myeloablative Post-Transplant
Conditioning And Bone Marrow Cell Infusion
Donor C57BL/6 (neonatal)
Recipient BALB/c
Donor (C57BL/6) Bone marrow cell infusion (50 x
106)
Heterotopic Heart TX
Total Lymphoid Irradiation10 Doses (240 cGy/dose)
D0 D1 D2 D4 D6 D8
D14 D15
ATG i.p. Injections
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Heterotopic Heart Graft Survival
Organ Donor CD1d-/- (BALB/c background)
or WT
BALB/c Recipient C57BL/6
BM Donor CD1d-/- (BALB/c background)
Or WT BALB/c