CDER Meeting: Surrogate Markers of Immunity

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CDER Meeting Surrogate Markers of Immunity

• Presenter Judith A. Britz, Ph.D.
• October 16, 2000

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(No Transcript)
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HIV Pathogenesis

• Cellular Immune Function Tests have Prognostic
  Value
• independent of CD4 Count
• Up to 1 year before CD4 Count Decline
• Progressive Loss of Function as measured by
  response to
• Mitogens
• Alloantigens
• Recall Antigens

Clerici et al. 1989. J. Clin. Invest. 84
1892 Dolan et al. 1995. J. Infect. Dis.17279
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Immune Reconstitution

• LPA Reactivity to HIV p24 rAg enhanced
• Long Term Non-Progressors
• Following early treatment of acute HIV infection
• Strengthened by treatment interruption (in some
  patients)

Rosenberg, E.S et al. 1997. Science 278
1447 Rosenberg, E.S. et al. 2000. Nature 408 523
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Lymphoproliferation (LPA)

• Traditional method for evaluating
• cell-mediated immune function
• Time-consuming 5-7 Days
• Radioactive
• Labor-intensive
• Not widely available
• Not standardized
• Shipping impact
• Not practical for clinical use

Betensky et al. 2000. Clin. Diag. Lab. Immunol.
7(5) 759
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Objectives

• Clinical Correlate of Cell-Mediated Immunity
• 24 Hours or less
• Non-Radioactive
• Whole Blood or PBMCs
• Cost Effective
• Adaptable to Test with Multiple Antigens
• Standardized

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4 hours to overnight
Lymphocyte Stimulation
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Comparison with LPA
ATP ng/mL In vitro CMI Overnight
DPM x 100 LPA assay 96 HRS
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Reference

• Sottong, P.R., J.A. Rosebrock, J.A. Britz, and
  T.R. Kramer. 2000.
• Measurement of T-lymphocyte responses in whole
  blood cultured using newly synthesized DNA and
  ATP.
• Clinical and Diagnostic Laboratory Immunology
  7(2) 307-311

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PHA Distribution of Normal and HIV Patients
Normal
HIV
Homi Farzadegan. Johns Hopkins. 2000. IHV Meeting.
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Measurement Of Cell Activation By Mitogens And
Recall Antigens
Therapy Changed
B.J. Loechelt, M. Chan Childrens National
Medical Center, Washington, D.C 2000. Manuscript
in Preparation.
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Measurement Of Cell Activation By Mitogens And
Recall Antigens
B.J. Loechelt, M. Chan Childrens National
Medical Center, Washington, D.C 2000. Manuscript
in preparation
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ATP
Cunningham-Rundles, S. and J. Cervia. Cornell
University School of Medicine. 2000. Manuscript
in preparation.
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Wahren, B. et al. Karolinska Institute. 2000. IHV
Meeting
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Lymphocyte Response
Cylex In Vitro CMI
Cytokine Assays
Lympho-proliferation
ATP 1/2 - 6 hours
Lymphocyte Stimulation
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Analytical Parameters

• Accuracy
• Precision
• Sensitivity
• Specificity
• Reproducibility
• Stability
• Standardization

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AIDS Patient Management
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Acknowledgements

• Susanna Cunnigham-Rundles Cornell
• Brett Loechelt George Washington
• Homi Farzadegan Johns Hopkins
• Britta Wahren Karolinska
• Tim Kramer USDA
• Peter Sottong Cylex
• Richard Kowalski Cylex
• Julie Woodcock Cylex