Antigen-Specific CD8+ T Cells Mediate a Peptide-Induced Fatal Syndrome

Abstract

Peptide immunotherapy both activates and suppresses the T cell response against known peptide Ags. Although pretreatment with VP2121–130 peptide inhibits the development of antiviral CTL specific for the immunodominant Db:VP2121–130 epitope expressed during acute Theiler’s murine encephalomyelitis virus infection, i.v. injection of this same peptide or MHC tetramers containing the peptide during an ongoing antiviral CTL response results in a peptide-induced fatal syndrome (PIFS) within 48 h. Susceptibility to PIFS is dependent on peptide-specific CD8+ T cells, varies among inbred strains of mice, and is not mediated by traditionally defined mechanisms of shock. Analyses using bone marrow chimeras and mutant mice demonstrate that susceptibility to PIFS is determined by the genotype of bone marrow-derived cells and requires the expression of perforin. Animals responding to peptide treatment with PIFS develop classical stress responses in the brain. These findings raise important considerations for the development of peptide therapies for active diseases to modify immune responses involving expanded populations of T cells. In summary, treatment with peptides or MHC-tetramers during a peptide-specific immune response can result in a fatal shock-like syndrome. Susceptibility to the syndrome is genetically determined, is mediated by CD8+ T cells, and requires expression of perforin. These findings raise concerns about the use of peptides and MHC tetramers in therapeutic schemes.

Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8+Cytotoxic T Cells

“…6) or serum histamine (data not shown). A previous study also reported animal deaths following injection of soluble VP2 121-130 into TMEV-infected B6 mice but did not mention any seizures or describe the cytokine environment (14). We thus compared the effects of injection of soluble VP2 121-130 versus VP2 121 -SP into TMEV-infected B6 mice at 6 days p.i.…”

“…This method of tolerance has advantages over the use of soluble peptides. In animal models of CD4 ϩ T-cell-mediated autoimmunity, it has been shown that soluble peptide injection can lead to anaphylactic shock (36) or other adverse reactions (14,22), and in a clinical trial, parenteral injection of peptide led to hypersensitivity reactions (16). Thus, ECDI-coupled cell tolerance is of possible interest for the treatment of human diseases.…”

Experimental Model Systems to Define Mechanisms of Immune-Mediated Blood Brain Barrier Disruption in Acute Disseminated Encephalomyelitis (ADEM) and Acute Hemorrhagic Leukoencephalitis (AHLE)

“…Another important aspect of the PIFS model is the observation that mice lacking major histocompatibility complex (MHC) class II, and thus CD4 T cells, IFN-R, TNF-, TNFR1, TNFR2, and TNFR1/TNFR2 still succumbed to the fatal syndrome. Inhibiting interleukin-1 and lymphotoxin-did not serve to protect the mice from PIFS (Johnson et al, 2005). Therefore, it appears that the cytokines and CD4 T cell subsets heavily studied in other model systems of immune-mediated CNS vascular permeability do not play a role in the development of fatal blood brain barrier disruption in the PIFS model.…”

“…While C57BL/6 mice are highly susceptible to PIFS, both FVB and 129 SvIm strains are significantly more resistant. Interestingly, this holds true despite these strains having a substantial population of antigen-specific CD8+ T cells (Johnson et al, 2005). Another important aspect of the PIFS model is the observation that mice lacking major histocompatibility complex (MHC) class II, and thus CD4 T cells, IFN-R, TNF-, TNFR1, TNFR2, and TNFR1/TNFR2 still succumbed to the fatal syndrome.…”

“…Therefore, it appears that the cytokines and CD4 T cell subsets heavily studied in other model systems of immune-mediated CNS vascular permeability do not play a role in the development of fatal blood brain barrier disruption in the PIFS model. However, removal of antigen-specific CD8+ T cells conferred protection, preventing mice from becoming moribund (Johnson et al, 2005). Suidan et al took this into consideration and investigated the contribution of the effector functions of CD8+ T cells, notably perforin and FasL, on disruption of the BBB and PIFS.…”