Evidence of an Immune-Mediated Mechanism for an Idiosyncratic Nevirapine-Induced Reaction in the Female Brown Norway Rat
Bibliographic record
Abstract
Previously, we reported a new animal model of an idiosyncratic drug reaction in which nevirapine causes a skin rash in some rats that has characteristics similar to the reaction that occurs in humans. Strong evidence that the reaction is immune-mediated was found; specifically, low-dose pretreatment induced tolerance, while with rechallenge, the time to onset decreased and the severity increased. Furthermore, splenocytes from rechallenged rats transferred rash susceptibility to naïve recipients. We now report the results of studies to explore the immune aspects of this reaction. T cells were found to play an important role, as demonstrated by their ability to adoptively transfer susceptibility to the skin reaction. Of these T cells, CD4+ cells are the likely effectors because they were capable of transferring susceptibility and the reaction was delayed in rats partially depleted of CD4+ T cells. In contrast, it appears that CD8+ T cells are not essential, as CD8+ T cells were unable to transfer sensitivity to a naïve animal and rats depleted of CD8+ T cells still developed skin rash. Unlike the penicillamine model, where we have demonstrated that the tolerance induced by low-dose treatment is immune-mediated, tolerance induced by low-dose nevirapine appears to be largely due to induction of metabolism as it can be overcome by inhibition of cytochrome P450. Pretreatment with the immunosuppressants, cyclosporine and tacrolimus, prevented the rash and even led to resolution of the rash during nevirapine treatment. These studies reinforce the hypothesis that the reaction in this model is similar to that which occurs in humans. In particular, the finding that CD4+ T cells may play a central role in this model fits with the observation that the incidence of idiosyncratic reactions to nevirapine in humans appears to be lower in patients with low CD4+ counts.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".