This document summarizes research on the immune response to cytomegalovirus (CMV) and cancer-testis antigens (CTAgs). It discusses how CMV elicits a massive immune response, occupying up to 40% of CD8+ T cells. This response declines with immunosuppression. It also explores using CMV-specific T cells for immunotherapy after stem cell transplantation. The document then examines CTAgs, which are expressed in cancers and elicit anti-tumor immune responses, but challenges remain in understanding their efficacy.
3. - HIV+ donors - Cloned HIV-specific CTL - Cloned TCR - cDNA from PBMC was probed with oligos for TCRs - Suggested effector frequency of 0.2 - 1%
4. Led to collaboration on use of new reagents to study T cell immune responses Viral Antigen Fluorescence T Cell
5. We could visualise HIV-specific T cells Altman, Moss et al Science. 1996 Oct 4;274(5284):94-6.Phenotypic analysis of antigen-specific T lymphocytes.
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7. Herpes viruses Group of eight viruses HSV I & II, EBV, VZV, CMV, HHV-6 HHV-7, HHV-8
13. Age Percentage of CD8+ T cell response Khan et al , J.I. 2004 The CD8-specific T cell response to CMV increases with age DE F P=0.0352 P0.0067 P=0.0159 P=0.07262 P=0.003
14. How does CMV change the memory and naïve T cell count in healthy people ? T cells Naive Memory
23. Sometimes the initial (primary) infection with CMV can cause clinical problems “ I though it was the end of my tennis. Even as a person I could feel myself changing. I just wanted to stay and home and not see anyone, not even my friends. But slowly I got better. I still have to be careful and I can’t train or work as hard as I once did” Justine Henin-Hardenne
28. CMV was a major cause of death in the early days of stem cells transplantation CMV pneumonitis
29. Patients have very few CMV-specific T cells in the first three months following SCT Time post-SCT Number of CMV-specific T cells
30. Is it possible to transfer T cells into the patient to correct the early period of immunodeficiency ? CMV-specific T cells
31. BMT is the ideal setting for adoptive transfer of T cells D D P P Time Following SCT, the patient is immunologically tolerant of cells taken from the donor
32. Use tetramers to bind to CMV-specific T cells in the donor Stain T cells FACS analysis T Cell PE
33. T cells that bind tetramer can be selected with magnetic beads T Cell PE
34. Transferred T cells can expand and clear CMV viraemia ( Cobbold et al, JEM 2005) 2.10 6 CMV-specific T cells were given 99.5% Pre-infusion blood sample 0% • Prior to infusion the patient had CMV viraemia • No CMV-specific T cells were present 0.5% 9 days later T cells were present and the patient became CMV negative Blood sample 9 days after infusion
51. Tumour regression following vaccination MAGE antigens in a melanoma patient Evolution of skin metastases on the leg of patient EB81 during treatment. van Baren N et al 2005 (A) (B) (C) (A) Before vaccination (B) After four vaccinations with ALVAC (after 3 months) (C) After 10 months
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54. PBMCs only PBMCs + RVRF PRE POST 0.05% 0.01% 0.00008 0.004 Example of CTAg-specific cell responses in myeloma CD8 IFN
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58. The CD8 response actually increases in the terminal stages of disease
59. MAGE – specific CD8 T cell clones can kill tumour when they are cloned in vitro (iii) (ii)
71. 2000- renal transplant patient developed melanoma in kidney and breast 2000 - another transplant patient 2 developed melanoma in kidney - Registry showed both patients had been transplanted from same patient in 1998 - This patient had received excision of 2.6mm melanoma in 1982 Tumour latency Mackie 2003
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If an antigen which had been labelled, for instance with a fluorescent dye, could be directly bound to T cells then the antigen-specific cells could be detected directly.
Once these complexes are made they can bind to a T cell specific for the peptide which was been inserted in the multimeric complex and then these T cells can be detected on a FACS machine by the fluoresecnce that they emit.
Once these complexes are made they can bind to a T cell specific for the peptide which was been inserted in the multimeric complex and then these T cells can be detected on a FACS machine by the fluoresecnce that they emit.
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