Tolerance Induction

Dr. S. StroberStanford University

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)

Total Lymphoid Irradiation

• Treatment for Hodgkin’s Disease• Safe and effective (10,000 patients )

• Multiple small doses of irradiation

• Targeted to lymph nodes, spleen , and thymus-other tissues shielded

• Outpatient procedure

Non-Myeloablative TLI/ATS ProtocolNon-Myeloablative TLI/ATS Protocol

ATS i.p. Injections

D-24 D-12 D-10 D-8 D-1 D0

Donor: C57BL/6 (H2b)Bone marrow

+ or - Spleen or

blood T cellsRecipient:

BALB/c

Total Lymphoid Irradiation:17 Doses (240 cGy/dose)

*Figure by A. Pillai MD

TLI + ATG Treated Mice are Resistant to GVHD

Lan F. et al., J. Immunol. 167, 2001

TLI/ATG Conditioning for Hematolymphoid Malignancies Using MRD/URD

ATG 1.5 mg/kg/day Day

0

GVHD prophylaxis

Day 180

Days -11 to -7

CSA

MMF

TLI 800 cGy over 10 fractionsDays -4 to -1Days -11 to -7

Infection Prophylaxis

HSV: if +ve acyclovir 400 mg BIDCMV: blood PCR weeklyEBV: blood PCR every 2 weeksPCP: Septra DS BID weekends D+42Fungus: if prior infection or URD

Lowsky R, et al., NEJM Sept 2005

Sykes and Spitzer, Nat. Med.11,1164: 2005

Non-Myeloablative Post-Transplant ConditioningAnd Bone Marrow Cell Infusion

Non-Myeloablative Post-Transplant ConditioningAnd Bone Marrow Cell Infusion

ATG i.p. Injections

D0 D1 D2 D4 D6 D8 D14 D15

Donor (C57BL/6)Bone marrow

cell infusion (50 x 106)Heterotopic

Heart TX

Donor:C57BL/6

(neonatal)

Recipient:BALB/c

Total Lymphoid Irradiation:10 Doses (240 cGy/dose)

Heterotopic Heart Graft SurvivalHeterotopic 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

0 25 50 75 100 1250

102030405060708090

100110

WT TLI+ATS+BMTx (n=19)

WT TLI+ATS (n=6)

CD1d-/- TLI+ATS+BMTx (n=6)

Days post-HTx