Immunoinhibitory DNA Vaccine Protects Against Autoimmune Diabetes Through cDNA Encoding a Selective CTLA-4 (CD152) Ligand
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Bibliographic record
Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4 or CD152) is a strong negative regulator of T cell activity. Like CD28 (a positive regulator) it binds to B7-1 and B7-2, and there is no known natural selective ligand. Monoclonal antibodies to CTLA-4 generally have a masking effect, enhancing rather than suppressing responses. However, a single amino acid substitution in B7-1 (W88 > A; denoted B7-1wa) abrogates binding to CD28 but not to CTLA-4. We constructed plasmids encoding B7-1 or B7-1wa, as cell-surface or Ig fusion proteins. In a bound state, B7-1-Ig enhanced CD3-mediated T cell activation, but B7-1wa-Ig was inhibitory, as expected of a CTLA-4 ligand. To alter immunity in vivo, we inoculated mice intramuscularly (i.m.) with a carcinoembryonic antigen (CEA) plasmid. Gene transfer was amplified by electroporation. Co-injection of a B7-1wa (membrane-bound form) plasmid blocked induction of anti-CEA immunity, whereas a B7-1 plasmid was stimulatory. We studied this DNA covaccination method in nonobese diabetic (NOD) mice with autoimmune diabetes. Delivery of either preproinsulin I (PPIns) or B7-1wa cDNA alone did not suppress the autoimmune anti-insulin response of spleen cells. However, co-delivery of B7-1wa and PPIns cDNA abrogated reactivity to insulin and ameliorated disease. Interferon-gamma and interleukin-4 were both depressed, arguing against a Th2 bias. Reactivity to glutamic acid decarboxylase 65, another major islet autoantigen, was not altered and suppressor cells were not identified, suggesting induction of tolerance to insulin by either T cell anergy or deletion. Selective engagement of CTLA-4 through gene transfer represents a novel and powerful way to block autoimmunity specifically.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it