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CD40-targeted peptide proposed for type 1 diabetes therapy lacks relevant binding affinity to its cognate receptor. Reply to Pagni PP, Wolf A, Lo Conte M et al [letter]

  • Gisela M. Vaitaitis
  • Michael H. Olmstead
  • Dan M. Waid
  • Jessica R. Carter
  • David H. WagnerJr.Email author
Letter
  • 71 Downloads

To the Editor: We appreciate the letter by Pagni et al [1] that comments on our previous publication [2]. However, rather than definitively demonstrating that the KGYY15 peptide does not work in pre-clinical studies, their report highlights the complexities of CD40 as a molecule and strengthens the need for a better understanding of CD40. It is easy to think that a molecule that has been studied for so long is fully understood when in reality the opposite is true.

The CD40 molecule has, over time, proven to be more complex than a simple cell-identifying molecule. Tone et al [3] demonstrated the existence of CD40 isoforms that were generated through alternative splicing of its RNA. We subsequently showed that there are differentially glycosylated forms of CD40 and those that are less glycosylated appear to represent a more active form of the protein [4]. In addition, we demonstrated that CD40 can form hybrid receptors with TNF-receptors 1 and 2. Further, we reported that CD40 interacts...

Keywords

Autoimmunity CD154 CD40 Therapeutic Type 1 diabetes 

Abbreviation

RAG

Recombination activating gene

Notes

Contribution statement

GMV was responsible for drafting the article and DHW revised it critically for important intellectual content. All authors approved the version to be published.

Duality of interest

DHW is the founder and Chief Science Officer of Op-T LLC. DMW is the Chief Financial Officer of Op-T LLC. GMV performs consulting work for Op-T LLC.

References

  1. 1.
    Pagni PP, Wolf A, Lo Conte M et al (2019) CD40-targeted peptide proposed for type 1 diabetes therapy lacks relevant binding affinity to its cognate receptor. Diabetologia.  https://doi.org/10.1007/s00125-019-4893-2
  2. 2.
    Vaitaitis GM, Olmstead MH, Waid DM, Carter JR, Wagner DH Jr (2014) A CD40-targeted peptide controls and reverses type 1 diabetes in NOD mice. Diabetologia 57(11):2366–2373.  https://doi.org/10.1007/s00125-014-3342-5 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tone M, Tone Y, Fairchild PJ, Wykes M, Waldmann H (2001) Regulation of CD40 function by its isoforms generated through alternative splicing. Proc Natl Acad Sci U S A 98(4):1751–1756.  https://doi.org/10.1073/pnas.98.4.1751 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Vaitaitis GM, Wagner DH Jr (2010) CD40 glycoforms and TNF-receptors 1 and 2 in the formation of CD40 receptor(s) in autoimmunity. Mol Immunol 47(14):2303–2313.  https://doi.org/10.1016/j.molimm.2010.05.288 CrossRefPubMedPubMedCentralGoogle Scholar
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    Vaitaitis GM, Wagner DH Jr (2012) Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity. PLoS One 7(6):e38708.  https://doi.org/10.1371/journal.pone.0038708 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Vaitaitis GM, Wagner DH Jr (2013) CD40 interacts directly with RAG1 and RAG2 in autoaggressive T cells and Fas prevents CD40-induced RAG expression. Cell Mol Immunol 10(6):483–489.  https://doi.org/10.1038/cmi.2013.24 CrossRefGoogle Scholar
  7. 7.
    An HJ, Kim YJ, Song DH et al (2011) Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation. J Biol Chem 286(13):11226–11235.  https://doi.org/10.1074/jbc.M110.208215 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Vaitaitis GM, Yussman MG, Wagner DH Jr (2019) A CD40 targeting peptide prevents severe symptoms in experimental autoimmune encephalomyelitis. J Neuroimmunol 332:8–15.  https://doi.org/10.1016/j.jneuroim.2019.03.013 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gisela M. Vaitaitis
    • 1
    • 2
  • Michael H. Olmstead
    • 3
    • 4
  • Dan M. Waid
    • 1
    • 2
  • Jessica R. Carter
    • 1
    • 2
    • 5
  • David H. WagnerJr.
    • 1
    • 2
    Email author
  1. 1.Webb-Waring CenterUniversity of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.AuroraUSA
  4. 4.PAREXEL InternationalWalthamUSA
  5. 5.SalemUSA

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