Immune & Thymic Peptides (Thymosin Alpha-1, LL-37) — References

Mirrored Reference Dossier

Parent Topic: Immune & Thymic Peptides (Thymosin Alpha-1, LL-37) | References Hub: 02 - Compounds & Molecules References MOC

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Landmark Peer-Reviewed Studies

1. Wu et al. (2013) — Critical Care (ETASS Trial)

• Citation: Wu, J., Zhou, L., Liu, J., Ma, G., Kou, Q., He, Z., Chen, J., Ou-Yang, B., Chen, M., Li, Y., Wu, X., Gu, B., Chen, L., Zou, Z., Qiang, X., Chen, Y., Lin, A., Zhang, G., & Guan, X. (2013). The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Critical Care, 17(1), R8.
• Identifiers: PMID: 23327199 (PubMed · Europe PMC) | PMCID: PMC3672506 (PMC Full Text) | DOI: 10.1186/cc11932 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Multicenter, randomized, controlled clinical trial across 6 tertiary ICUs ($N=361$) evaluating subcutaneous Thymosin Alpha-1 ($\text{T}\alpha 1$) ($1.6\text{ mg}$ twice daily for 5 days, then once daily for 2 days) vs. control in patients with severe sepsis.
• Key Quantitative Outcomes: Thymosin Alpha-1 reduced 28-day all-cause mortality from $35.0\%$ in the control group to $26.0\%$ in the $\text{T}\alpha 1$ group ($\text{Relative Risk }0.74$; log-rank $p=0.049$, adjusted $p=0.032$), reduced SOFA organ failure scores, and significantly increased monocyte mHLA-DR antigen presentation expression on days 3 and 7 ($+8.9\%$ vs. $+2.1\%,p=0.017$), reversing sepsis-induced immunoparalysis.

2. Romani et al. (2006) — Blood

• Citation: Romani, L., Bistoni, F., Perruccio, K., Montagnoli, C., Gaziano, R., Bozza, S., Bonifazi, P., Bistoni, G., Rasi, G., Velardi, A., Fallarino, F., Garaci, E., & Puccetti, P. (2006). Thymosin $\alpha 1$ activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood, 108(7), 2265–2274.
• Identifiers: PMID: 16741252 (PubMed · Europe PMC) | DOI: 10.1182/blood-2006-02-004762 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Human hematopoietic stem cell transplant recipient dendritic cell and murine functional immunology study dissecting the dual immunomodulatory mechanism of Thymosin Alpha-1.
• Key Quantitative Outcomes: Demonstrated that $\text{T}\alpha 1$ signals simultaneously through TLR9 and TLR2 via MyD88 to induce Indoleamine 2,3-Dioxygenase (IDO1) in plasmacytoid dendritic cells, driving the differentiation of ${\text{CD4}}^{+}{\text{CD25}}^{+}{\text{FoxP3}}^{+}$ Regulatory T-cells ($\text{Tregs}$) and IL-10 production while preserving pathogen-clearing $\text{Th1}$ immunity—preventing lethal graft-versus-host hyperinflammation without causing generalized immunosuppression.

3. Liu et al. (2006) — Science

• Citation: Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., Kamen, D. L., Wagner, M., Bals, R., Steinmeyer, A., Zügel, U., Gallo, R. L., Eisenberg, D., Hewison, M., Hollis, B. W., Adams, J. S., Bloom, B. R., & Modlin, R. L. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 311(5768), 1770–1773.
• Identifiers: PMID: 16497887 (PubMed · Europe PMC) | DOI: 10.1126/science.1123933 (DOI · SciDB · Scholar)
• Study Design & Sample Size: DNA microarray transcriptomics and human monocyte/macrophage infection study with Mycobacterium tuberculosis.
• Key Quantitative Outcomes: Proved that TLR2/1 activation of human macrophages upregulates expression of the Vitamin D Receptor (VDR) and CYP27B1 ($1\alpha$-hydroxylase), which converts $25(\text{OH}){\text{D}}_3$ into $1,25(\text{OH}{)}_2{\text{D}}_3$ to directly induce the cathelicidin (CAMP / LL-37) gene by $>10\text{-fold}$ ($p<0.001$), reducing intracellular M. tuberculosis viability by $-60\text{ to }-75\%$.

4. Overhage et al. (2008) — Infection and Immunity

• Citation: Overhage, J., Campisano, A., Bains, M., Torfs, E. C., Rehm, B. H., & Hancock, R. E. (2008). Human host defense peptide LL-37 prevents bacterial biofilm formation. Infection and Immunity, 76(9), 4176–4182.
• Identifiers: PMID: 18591225 (PubMed · Europe PMC) | PMCID: PMC2519406 (PMC Full Text) | DOI: 10.1128/IAI.00318-08 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Confocal laser scanning microscopy flow-chamber biofilm assay and DNA microarray analysis against Pseudomonas aeruginosa.
• Key Quantitative Outcomes: At sub-inhibitory physiological concentrations ($0.5\mu \text{g/mL}$, or $1/128$ of the planktonic MIC), LL-37 inhibited new bacterial biofilm formation by $-50\text{ to }-80\%$ and reduced the thickness of pre-established mature biofilms by $-60\%$ ($p<0.001$) by downregulating Las and Rhl quorum-sensing systems, stimulating twitching motility dispersal, and suppressing flagellar attachment genes.