Since 1963, Adler and his colleagues had dedicated their publications to the explanation of the biphasic immune response, this comprised a deep understanding of the early wave of IgM secretion, followed by a later wave of specific IgG occurring in immunized animals.

 

In fact, they noticed that infection with a T2 bacteriophage of peritoneal exudate cells triggers an immune response in lymph nodes of non-immune animals, when the two populations subsets are exposed together. Although the IgGs were from the allotype of the donor lymph nodes, the IgMs proved to be from the allotype of the donor exudate cells.

 

Adler et al. therefore questioned the existence of a specific messenger, making the connection between different immune cell subsets.

 

 

Since the exudate cells were rich in macrophages, and if the cell of origin was the macrophage that had ingested T2, then the question arose why this cell had to produce messenger RNA relevant for immunoglobulin synthesis when it did not produce such globulins (1).

 

By the end of 1970, and with the wish to answer this riddle, many teams (2, 3) concluded that the macrophage was involved in antigen processing, antigen concentration, presentation of the antigen to the precursor cell, or in transfer of genetic information specifying immunoglobulin structure to the precursor cell.

 

A year later, Gery et al. demonstrated that macrophages release one or more mitogenic substances that act on T lymphocytes, greatly potentiating their response to immunogens when activated with lipopolysaccharides. They proposed the term LAF for "lymphocyte-activating factor" for the potentiating activity in question. If they initially recognized that LAF may prove to be heterogeneous, first fractionation studies rapidly suggested that the team was confronted with a single substance (4).

 

At the same moment, Elisha Atkins was working on a different topic. Curious about fever as a consequence of virus and bacterial infection, he was trying to identify and understand the compound involved. This endogenous pyrogen was soon established as a species-specific entity, produced by polymorphonuclear leukocytes and which requires a stimulus to be produced (5).

 

Subjugated by this discovery, Charles Dinarello decided to set-up a radioimmunoassay to detect and accurately measure the circulating leukocytic pyrogen (LP) during fever in humans (6), so replacing the limited Atkins’ bio-assay. Using a macrophage-dependent T-cell assay developed by Lanny Rosenwasser, Charles tested LP on mouse lymphocytes. After two years of repeated testing, he concluded that LP and LAF were the same molecule (7).

 

 

The term interleukin-1 (IL-1) now refers to the originally described endogenous pyrogen and lymphocyte-activating factor. Unlike other cytokine families, the IL-1 family is the mediator of the inflammatory response, at both the receptor and nuclear levels. Members of the IL-1 family of receptors contain activators and suppressors of inflammation and are now the most studied interleukin group.

 

In 1985, March et al. (8) isolated cDNA libraries from LPS-stimulated macrophages and discovered that IL-1 consists of two distinct proteins, called interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β).

 

And the latter hadn't said its last word.

 

IL-1β is a cytokine of 269 amino-acids with a molecular weight of 30,7 kDa. It is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. This cytokine is synthetized as a precursor (proIL-1β) and then cleaved in its biologically active form (17,4 kDa) by Caspase-1, just prior to aspartate residues (9).

 

Caspase-1 is part of the inflammasome, a complex formed as a result of the recognition of various inflammatory signals by « NOD-like receptor family, pyrin domain containing 3 » (NLRP3) or cryopyrin (10).

 

Mutations on NLRP3 genes cause spontaneous activation of the NLPR3 inflammasome and lead to excessive IL-1β secretion. This discovery is the basis of a class of chronic inflammatory diseases, uniquely mediated by IL-1β, and known as auto-inflammatory diseases, such as cryopyrin-associated periodic syndrome (CAPS), gout, and DIRA syndrome.

 

But IL-1β is also part of the complex puzzle of other diseases, playing a role in:

• type 2 diabetes (11)
• cancer (12)
• liver fibrosis (13)
• rheumatoid arthritis (14)
• COVID-19 (15)
• and potentially many others.

 

Canakinumab is a fully human monoclonal antibody directed against human interleukin-1 beta (IL-1ß). Canakinumab binds with high affinity to human IL-1 beta and neutralizes its biological activity by inhibiting its interaction with IL-1 receptors, thus preventing the synthesis of inflammatory mediators : by inhibiting interleukin 1beta, this therapeutic monoclonal antibody, developed by Novartis, reduces interleukin 6 levels and hepatic synthesis of C-Reactive Protein (CRP) and fibrinogen.

 

Following Canakinumab marketing authorization for the treatment of Cryopyrin-associated autoinflammatory syndromes (CAPS) - rare diseases related to a defect in the cryopyrin protein - Novartis decided to reposition its antibody in non-small cell lung cancer (NSCLC) indication. Unfortunately, after two unsuccessful large-scale randomized Phase III clinical trials in 2021, the new Canopy A study was another repurposing setback for Novartis in 2022.

 

Gevokizumab, originally developed by XOMA, has also failed to demonstrate significant efficacy as a single-agent therapy. However, the treatment of WT mice (4T1 breast tumors) first with anti-IL-1β monoclonal antibodies and then with anti-PD-1 mAbs completely halted tumor progression in 2019 (16). These data were confirmed by Novartis during the AACR in 2023 on humanized mice, and further study revealed that cancer-associated fibroblasts (CAFs) were the cell type most affected by canakinumab or gevokizumab treatment. Inhibition of IL1β led to phenotypic changes in CAF populations, particularly those with the capacity to influence immune cell recruitment.

 

 

REFERENCES

 

 (1) F. L. Adler, M. Fishman and S. Dray. Antibody Formation Initiated in Vitro III. Antibody Formation and Allotypic Specificity Directed by Ribonucleic Acid from Peritoneal Exudate Cells. J Immunol October 1, 1966, 97 (4) 554-558;

 

(2) Donald E. Mosier. A Requirement for Two Cell Types for Antibody Formation in vitro. Science  22 Dec 1967: Vol. 158, Issue 3808, pp. 1573-1575. DOI: 10.1126/science.158.3808.1573.

 

 (3) R. W. DUTTON, MARGARET M. MCCARTHY, R. I. MISHELL, AND D. J. RAIDT Cell Components in the Immune Response IV. Relationships and Possible Interactions. Received February 17, 1970

 

(4) Gery I, Gershon RK, Waksman BH (July 1972). "Potentiation of the T-lymphocyte response to mitogens. I. The responding cell". The Journal of Experimental Medicine. 136 (1): 128 42. doi:10.1084/jem.136.1.128. PMC 2139184. PMID 5033417.

 

(5) Bodel P, Atkins E. Human leukocyte pyrogen producing fever in rabbits. Proc Soc Exp Biol Med. 1966;121(3):943-946. doi:10.3181/00379727-121-30931

 

(6) Dinarello, C. A., Renfer, L., & Wolff, S. M. (1977). Human leukocytic pyrogen: purification and development of a radioimmunoassay. Proceedings of the National Academy of Sciences, 74(10), 4624–4627. doi:10.1073/pnas.74.10.4624

 

(7) L J Rosenwasser, C A Dinarello, A S Rosenthal; Adherent cell function in murine T-lymphocyte antigen recognition. IV. Enhancement of murine T-cell antigen recognition by human leukocytic pyrogen.. J Exp Med 19 September 1979; 150 (3): 709–714. doi: https://doi.org/10.1084/jem.150.3.709

 

(8) March, C., Mosley, B., Larsen, A. et al. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 315, 641–647 (1985). https://doi.org/10.1038/315641a0

 

(9) R. A. Black, S. R. Kronheim, J. E. Merriam, C. J. March et T. P. Hopp, « A pre-aspartate-specific protease from human leukocytes that cleaves pro-interleukin-1 beta », Journal of Biological Chemistry, vol. 264, no 10,‎ 5 avril 1989, p. 5323-5326

 

(10) Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417-426. doi:10.1016/s1097-2765(02)00599-3

 

(11) Nils Welsh, Miriam Cnop, Ilham Kharroubi, Marco Bugliani, Roberto Lupi, Piero Marchetti, Décio L. Eizirik. Is There a Role for Locally Produced Interleukin-1 in the Deleterious Effects of High Glucose or the Type 2 Diabetes Milieu to Human Pancreatic Islets? Diabetes Nov 2005, 54 (11) 3238-3244; DOI: 10.2337/diabetes.54.11.3238

 

(12) Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. doi:10.1038/nature07205

 

(13) Gieling RG, Wallace K, Han YP. Interleukin-1 participates in the progression from liver injury to fibrosis. Am J Physiol Gastrointest Liver Physiol. 2009;296(6):G1324-G1331. doi:10.1152/ajpgi.90564.2008

 

(14) Bresnihan, B., Alvaro‐Gracia, J.M., Cobby, M., Doherty, M., Domljan, Z., Emery, P., Nuki, G., Pavelka, K., Rau, R., Rozman, B., Watt, I., Williams, B., Aitchison, R., McCabe, D. and Musikic, P. (1998), Treatment of rheumatoid arthritis with recombinant human interleukin‐1 receptor antagonist. Arthritis & Rheumatism, 41: 2196-2204. doi:10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2

 

(15) Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):327-331. doi:10.23812/CONTI-E

 

(16) Kaplanov I, Carmi Y, Kornetsky R, Shemesh A, Shurin GV, Shurin MR, Dinarello CA, Voronov E, Apte RN. Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1361-1369. doi: 10.1073/pnas.1812266115. Epub 2018 Dec 13. PMID: 30545915; PMCID: PMC6347724.