Emerging Science, Emerging Ethical Issues: Who Should Fund Innate Alloimmunity-suppressing Drugs ?
Bibliographic record
Abstract
An emerging body of evidence suggests that the innate immune system plays a critical role in allograft rejection. Any injury to the donor organ, e.g. the reperfusion injury, induces an inflammatory milieu in the allograft which appears to be the initial event for activation of the innate immune system. Injury-induced intragraft damage- associated molecular patterns (DAMPs) are recognized by donor-derived and recipient-derived, TLR4/2-bearing immature dendritic cells (iDCs). After recognition, these cells mature and initiate allorecognition/alloactivation in the lymphoid system of the recipient. Indeed, the key "innate" event, leading to activation of the adaptive alloimmune response, is the injury-induced, TLR4-triggered, and NFkappaB-mediated maturation of DCs ("innate alloimmunity"). Time-restricted treatment of innate immune events would include 1) treatment of the donor during organ removal, 2) in-situ/ex-vivo treatment of the donor organs alone, and 3) treatment of the recipient during allograft reperfusion and immediately postoperatively. Treatment modalities would include 1) minimization of the oxidative allograft injury with the use of antioxidants; 2) prevention of the TLR4-triggered maturation of DCs with the use of TLR4-antagonists; 3) inhibition of complement activation with the use of complement inhibiting agents. According to data from clinical and experimental studies it can be assumed that successful suppression of innate alloimmune events results in either subsequent significant reduction in, or even complete avoidance of the currently applied adaptive alloimmunity-suppressing drugs. However, in view of the time-restricted period of treatment, and the fear to potentially destroy its own business with currently applied alloimmunity-suppressing drugs, the pharmaceutical industry is still, but quite legitimately, reluctant to invest in the high cost of clinical development of those drugs for transplant patients because there are no marketing interests. On the other hand, clinical development of innate alloimmunity-suppressing drugs is urgently warranted. But: Who should fund? In this article, three options are explored which may contribute to a solution of the problem: 1) provision of incentives to companies for drug development; 2) conduction of clinical trials in developing countries; and 3) creation of a public-private professional partnership in analogy to the "European Rare Diseases Therapeutic Initiative" (ERDITI). We suggest and recommend the creation of such a partnership which may be called: "The European Initiative for the Suppression of Innate Alloimmunity" ("EISIA"). In analogy to ERDITI, the main goals of this organization should be:--to provide a streamlined facilitated process of collaboration between Academic Teams/Transplant Centres, Study Groups, and Pharma Companies to develop innate alloimmunity-suppressing drugs;--to give Academic Teams/Transplant Centres facilitated access to a large variety of compounds, developed by companies for other indications, which can be evaluated pre-clinically and, if warranted, clinically;--to guarantee the continuity all the way from research to development and commercialisation of the drug. If preclinical studies uncover the potential of a compound for suppressing innate alloimmune events, the Pharma Partner who has rights to this compound will either develop himself the drug for organ transplantation indication or allow its development by the academic team or a third party if he has no intentions of developing himself.
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How this classification was reachedexpand
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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.003 | 0.003 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.003 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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; both teacher heads agree on what is shown here.
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".