Immune selective anti-inflammatory derivatives

Immune Selective Anti-Inflammatory Derivatives (ImSAIDs)

Background

Immune Selective Anti-Inflammatory Derivatives (ImSAIDs) are a class of peptides discovered to have diverse biological properties, including potent anti-inflammatory properties. ImSAIDs work by altering the activation and migration of inflammatory cells (leukocytes, white blood cells), which are immune cells responsible for triggering and amplifying the inflammatory response. Recent attention has focused on leukocytes as new targets for developing anti-inflammatory drugs [http://www.nature.com/ni/journal/v6/n12/pdf/ni1275.pdf] [http://www.pubmedcentral.gov/picrender.fcgi?artid=270694&blobtype=pdf] .

The term Immune Selective Anti-Inflammatory Dervitatives (ImSAIDs) was coined by Craig Woods, a veterinarian working in the field of immunobiology, to describe the new mechanism by which these peptides acheived their effects. The peptide ImSAIDs are unrelated to steroid hormones or non steroidal anti-inflammatories (NSAIDs). The ImSAIDs were discovered by scientists evaluating biological properties of the submandibular gland and saliva. Early work in this area demonstrated that the submandibular gland released a host of factors which regulate systemic systemic immune and inflammatory reactions [ [http://www.ncbi.nlm.nih.gov/pubmed/9130570?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Davison JS, Befus AD.] A peptide from the submandibular glands modulates inflammatory responses. Int Arch Allergy Immunol. 1997 May-Jul;113(1-3):337-8.] [ [http://www.ncbi.nlm.nih.gov/pubmed/7802923?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS, Befus AD.] Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today. 1994 Nov;15(11):527-32. Review ] .

It is now well accepted that the immune, nervous and endocrine systems communicate and interact to control and modulate inflammation and tissue repair. One of the neuroendocrine pathways, when activated, results in the release of immune regulating peptides from the submandibular gland upon neuronal stimulation from sympathetic nerves. This pathway or communication is referred to as the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, a regulatory axis that plays a role in the systemic control of inflammation [ [http://www.ncbi.nlm.nih.gov/pubmed/7802923?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS, Befus AD.] Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today. 1994 Nov;15(11):527-32. Review. ] .

Early work in identifying factors that played a role in the CST-SMG axis lead to the discovery of a seven amino acid peptide, called the submandibular gland peptide-T (SGP-T). SGP-T was demonstrated to have biological activity and thermoregulatory properties related to endotoxin exposure [ [http://www.ncbi.nlm.nih.gov/pubmed/9250374?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Malkinson T, Cooper KE, Davison JS.] Submandibular glands: novel structures participating in thermoregulatory responses. Can J Physiol Pharmacol. 1997 May;75(5):407-13. ] . SGP-T, an isolate of the submandibular gland, also demonstrated its immunoregulatory properties and potential role in modulating the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, and subsequently was shown to play an important role in the control of inflammation [ [http://www.ncbi.nlm.nih.gov/pubmed/7802923?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS, Befus AD.] Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today. 1994 Nov;15(11):527-32. Review. ] .

Similar to aspirin or penicillin, SGP-T served as the foundation for the development of a new therapeutic class of molecules and served as the basis to look for more biologically active fractions, and in particular fractions or derivatives which possessed universal anti-inflammatory properties with oral bioavailability [ [http://www.ncbi.nlm.nih.gov/pubmed/9130570?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Davison JS, Befus AD.] A peptide from the submandibular glands modulates inflammatory responses. Int Arch Allergy Immunol. 1997 May-Jul;113(1-3):337-8. ] . One SGP-T derivative shown to have potent anti-inflammatory properties is the three amino acid sequence, phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG).

Suspected Evolutionary Purpose: One proposed theory about the evolution of this class of peptides is to control oral and systemic inflammation. The oral cavity and intestinal tract are hostile environments for tissues, subject to constant physical, chemical, and pathogen challenges which provoke inflammation. The evolution of biological factors to maintain homeostasis of this tissue environment and avoid uncontrolled inflammation or immunosuppression would be of tremendous value. SGP-T, and its likely tripeptide fractions (feG, FEG, etc.) would satisfy this theory and help maintain a control on inflammation.

Mode of action and biological effects

Cellular Effects of feG: The cellular effects of the ImSAIDs are characterized in a number of publications. feG and related peptides are known to modulate leukocyte (white blood cells) activity by influencing cell surface receptors (see cell receptor) to inhibit excessive activation and tissue infiltration [ [http://www.ncbi.nlm.nih.gov/pubmed/18492254?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Christie E, Davison JS.] The tripeptide feG inhibits leukocyte adhesion. J Inflamm (Lond). 2008 May 20;5:6. ] . One lead ImSAID, the tripeptide FEG (Phe-Glu-Gly) and its D-isomer (see Isomer) feG are known to alter leukocyte adhesion involving actions on αMβ2 integrin, and inhibit the binding of CD16b (FCyRIII) antibody to human neutrophils. These actions suggest the ImSAIDs may act on several distinct recognition sites and have multiple modes of action [ [http://www.ncbi.nlm.nih.gov/pubmed/18492254?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Christie E, Davison JS.] The tripeptide feG inhibits leukocyte adhesion. J Inflamm (Lond). 2008 May 20;5:6. ] , [ [http://www.ncbi.nlm.nih.gov/pubmed/18605243?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS.] Molecular characteristics of the tripeptide feG accounting for different biological activities. Proc West Pharmacol Soc. 2007;50:101-4. ] . feG has also been shown to decrease circulating neutrophil and eosinophil accumulation [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15549777&query_hl=2&itool=pubmed_docsum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25. ] , decrease intracellular oxidative activity (see Oxidative burst [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16776845&query_hl=2&itool=pubmed_docsum Mathison RD, Davison JS.] The Tripeptide feG Regulates the Production of Intracellular Reactive Oxygen Species by Neutrophils. J Inflamm (Lond). 2006 Jun 15;3(1):9 ] ), reduced the expression of CD49d after antigen exposure.

Studies suggest that feG and related peptides probably exert their anti-allergic actions via cellular events as they decrease anaphylactic events such as hypotension, intestinal motility and vascular permeability [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=9700752&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Moore G, Scott B, Davison JS.] Attenuation of intestinal and cardiovascular anaphylaxis by the salivary gland tripeptide FEG and its D-isomeric analog feG. Peptides. 1998;19(6):1037-42. ] , [Turesin F, Sadr A, Davison JS, Mathison R: The tripeptide FEG ameliorates systemic inflammatory responses to rat intestinal anaphylaxis. BMC Physiol 2002, 2:13] , and likely achieve these results by reducing leukocyte adhesion (see cell adhesion) and extravasation [ [http://www.ncbi.nlm.nih.gov/pubmed/15549777?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25. ] see Leukocyte extravasation.

Biological Effects: The biological activity of feG and FEG, and other ImSAIDs translate into the following general biological effects:

modulate the activation and chemotaxis of granulocytes [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16581192&query_hl=2&itool=pubmed_docsum Bao F, John SM, Chen Y, Mathison RD, Weaver LC.] The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. Neuroscience. 2006 Jul 7;140(3):1011-22. Epub 2006 Apr 3. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=12659660&query_hl=2&itool=pubmed_docsum Mathison RD, Befus AD, Davison JS, Woodman RC] . Modulation of neutrophil function by the tripeptide feG. BMC Immunol. 2003 Mar 4;4:3. Epub 2003 Mar 4. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11599779&query_hl=2&itool=pubmed_docsum Mathison R, Woodman R, Davison JS.] Regulation of leukocyte adhesion to heart by the tripeptides feG and feG(NH2). Can J Physiol Pharmacol. 2001 Sep;79(9):785-92. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15549777&query_hl=2&itool=pubmed_docsum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25. ] , reduce the production of reactive oxygen species [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16776845&query_hl=2&itool=pubmed_docsum Mathison RD, Davison JS.] The Tripeptide feG Regulates the Production of Intracellular Reactive Oxygen Species by Neutrophils. J Inflamm (Lond). 2006 Jun 15;3(1):9 ] , reduce the effects of endotoxin [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11903921&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Tan D, Scott B, Davison JS.] The tripeptide feG reduces endotoxin-provoked perturbation of intestinal motility and inflammation. Neurogastroenterol Motil. 2001 Dec;13(6):599-603. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11104835&query_hl=2&itool=pubmed_docsum Tan D, Rougeot C, Davison JS, Mathison R.] The carboxamide feG(NH2) inhibits endotoxin perturbation of intestinal motility. Eur J Pharmacol. 2000 Dec 8;409(2):203-5. ] reduce allergic (see allergic reaction) and anaphylactic reactions including type I immediate hypersensitivity and IgE (see Immunoglobulin E ) mediated reactions [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=9700752&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Moore G, Scott B, Davison JS.] Attenuation of intestinal and cardiovascular anaphylaxis by the salivary gland tripeptide FEG and its D-isomeric analog feG. Peptides. 1998;19(6):1037-42. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11306968&query_hl=2&itool=pubmed_docsum Dery RE, Mathison R, Davison J, Befus AD.] Inhibition of allergic inflammation by C-terminal peptides of the prohormone submandibular rat 1 (SMR-1). Int Arch Allergy Immunol. 2001 an-Mar;124(1-3):201-4. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11793968&query_hl=2&itool=pubmed_docsum Mathison RD, Davison JS, Befus AD.] The tripeptide feG reduces perturbation of intestinal motility provoked by anaphylaxis. Proc West Pharmacol Soc. 2001;44:157-8. ] ,reduce lung eosinophil infiltration in feline asthma [Declue AE, Schooley EK, Reinero CR. FEG-COOH tripeptide attenuates allergen-induced eosinophilic airway inflammation in a model of feline asthma. J Vet Int Med. 2007;21 (Abst). ]

Biological Activity of Various Known ImSAID Tripeptides

The table represents a few tripeptides that have been characterized for inhibiting antigen induced intestinal anaphylaxis in vitro. The model measured the contractile response to ovalbumin (OA) divided by contractile response to Urecholine. Peptide sequences are designated by single letter amino acid designation or code, lower case represents the d-isomer [US patent # 6,658,403. ] .

Potential Therapeutic Applications

The anti-inflammatory effects of the ImSAIDs appear to be quite broad and have been evaluated in a variety of disease models. feG and FEG have been shown to have prophylactic and/or therapeutic benefits in disease models involving endotoxemia [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11903921&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Tan D, Scott B, Davison JS.] The tripeptide feG reduces endotoxin-provoked perturbation of intestinal motility and inflammation. Neurogastroenterol Motil. 2001 Dec;13(6):599-603. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11104835&query_hl=2&itool=pubmed_docsum Tan D, Rougeot C, Davison JS, Mathison R.] The carboxamide feG(NH2) inhibits endotoxin perturbation of intestinal motility. Eur J Pharmacol. 2000 Dec 8;409(2):203-5. ] , spinal trauma (see spinal cord injury) [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16581192&query_hl=2&itool=pubmed_docsum Bao F, John SM, Chen Y, Mathison RD, Weaver LC.] The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. Neuroscience. 2006 Jul 7;140(3):1011-22. Epub 2006 Apr 3. ] , pancreatitis [ [http://www.ncbi.nlm.nih.gov/pubmed/18308855?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Rifai Y, Elder AS, Carati CJ, Hussey DJ, Li X, Woods CM, Schloithe AC, Thomas AC, Mathison RD, Davison JS, Toouli J, Saccone GT.] The tripeptide analog feG ameliorates severity of acute pancreatitis in a caerulein mouse model. Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G1094-9. ] , asthma [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15549777&query_hl=2&itool=pubmed_docsum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25. ] , allergic and anaphylactic reactions [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=9700752&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Moore G, Scott B, Davison JS.] Attenuation of intestinal and cardiovascular anaphylaxis by the salivary gland tripeptide FEG and its D-isomeric analog feG. Peptides. 1998;19(6):1037-42. ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11306968&query_hl=2&itool=pubmed_docsum Dery RE, Mathison R, Davison J, Befus AD.] Inhibition of allergic inflammation by C-terminal peptides of the prohormone submandibular rat 1 (SMR-1). Int Arch Allergy Immunol. 2001 an-Mar;124(1-3):201-4. ] .

Potential Veterinary Applications:

IMULAN BioTherapeutics is undertaking steps to further develop the ImSAIDs for feline asthma, stomatitis, atopic dermatitis, equine laminitis, and sepsis, equine colic, and canine osteoarthritis.

External Links

* [http://www.imulan.com IMULAN BioTherapeutics]

References

1. http://www.nature.com/ni/journal/v6/n12/pdf/ni1275.pdf

2. http://www.pubmedcentral.gov/picrender.fcgi?artid=270694&blobtype=pdf

3. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16581192&query_hl=2&itool=pubmed_docsum Bao F, John SM, Chen Y, Mathison RD, Weaver LC.] The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. Neuroscience. 2006 Jul 7;140(3):1011-22. Epub 2006 Apr 3.

4. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=12659660&query_hl=2&itool=pubmed_docsum Mathison RD, Befus AD, Davison JS, Woodman RC] . Modulation of neutrophil function by the tripeptide feG. BMC Immunol. 2003 Mar 4;4:3. Epub 2003 Mar 4.

5. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11599779&query_hl=2&itool=pubmed_docsum Mathison R, Woodman R, Davison JS.] Regulation of leukocyte adhesion to heart by the tripeptides feG and feG(NH2). Can J Physiol Pharmacol. 2001 Sep;79(9):785-92.

6. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15549777&query_hl=2&itool=pubmed_docsum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25.

7. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16776845&query_hl=2&itool=pubmed_docsum Mathison RD, Davison JS.] The Tripeptide feG Regulates the Production of Intracellular Reactive Oxygen Species by Neutrophils. J Inflamm (Lond). 2006 Jun 15;3(1):9

8. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11903921&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Tan D, Scott B, Davison JS.] The tripeptide feG reduces endotoxin-provoked perturbation of intestinal motility and inflammation. Neurogastroenterol Motil. 2001 Dec;13(6):599-603.

9. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11104835&query_hl=2&itool=pubmed_docsum Tan D, Rougeot C, Davison JS, Mathison R.] The carboxamide feG(NH2) inhibits endotoxin perturbation of intestinal motility. Eur J Pharmacol. 2000 Dec 8;409(2):203-5.

10. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=9700752&query_hl=2&itool=pubmed_docsum Mathison R, Lo P, Moore G, Scott B, Davison JS.] Attenuation of intestinal and cardiovascular anaphylaxis by the salivary gland tripeptide FEG and its D-isomeric analog feG. Peptides. 1998;19(6):1037-42.

11. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11306968&query_hl=2&itool=pubmed_docsum Dery RE, Mathison R, Davison J, Befus AD.] Inhibition of allergic inflammation by C-terminal peptides of the prohormone submandibular rat 1 (SMR-1). Int Arch Allergy Immunol. 2001 an-Mar;124(1-3):201-4.

12. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=11793968&query_hl=2&itool=pubmed_docsum Mathison RD, Davison JS, Befus AD.] The tripeptide feG reduces perturbation of intestinal motility provoked by anaphylaxis. Proc West Pharmacol Soc. 2001;44:157-8.

13. [http://www.ncbi.nlm.nih.gov/pubmed/18492254?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Christie E, Davison JS.] The tripeptide feG inhibits leukocyte adhesion. J Inflamm (Lond). 2008 May 20;5:6.

14. [http://www.ncbi.nlm.nih.gov/pubmed/18605243?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS.] Molecular characteristics of the tripeptide feG accounting for different biological activities. Proc West Pharmacol Soc. 2007;50:101-4.

15. [http://www.ncbi.nlm.nih.gov/pubmed/18308855?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Rifai Y, Elder AS, Carati CJ, Hussey DJ, Li X, Woods CM, Schloithe AC, Thomas AC, Mathison RD, Davison JS, Toouli J, Saccone GT.] The tripeptide analog feG ameliorates severity of acute pancreatitis in a caerulein mouse model. Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G1094-9.

16. [http://www.ncbi.nlm.nih.gov/pubmed/9130570?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Davison JS, Befus AD.] A peptide from the submandibular glands modulates inflammatory responses. Int Arch Allergy Immunol. 1997 May-Jul;113(1-3):337-8.17. [http://www.ncbi.nlm.nih.gov/pubmed/7802923?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS, Befus AD.] Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today. 1994 Nov;15(11):527-32. Review

18. [http://www.ncbi.nlm.nih.gov/pubmed/9250374?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison RD, Malkinson T, Cooper KE, Davison JS.] Submandibular glands: novel structures participating in thermoregulatory responses. Can J Physiol Pharmacol. 1997 May;75(5):407-13.

19. Turesin F, Sadr A, Davison JS, Mathison R: The tripeptide FEG ameliorates systemic inflammatory responses to rat intestinal anaphylaxis. BMC Physiol 2002, 2:13

20. [http://www.ncbi.nlm.nih.gov/pubmed/15549777?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Dery RE, Ulanova M, Puttagunta L, Stenton GR, James D, Merani S, Mathison R, Davison J, Befus AD.] Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway. Eur J Immunol. 2004 Dec;34(12):3315-25.

21. US patent # 6,658,403.

22. [http://www.ncbi.nlm.nih.gov/pubmed/7802923?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mathison R, Davison JS, Befus AD.] Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors. Immunol Today. 1994 Nov;15(11):527-32. Review.

23. Declue AE, Schooley EK, Reinero CR. FEG-COOH tripeptide attenuates allergen-induced eosinophilic airway inflammation in a model of feline asthma. J Vet Int Med. 2007;21 (Abst).