×
Home
Current Archive Submission Guidelines
News Contact
Review paper

Selective Immunotherapy by Engineered Chimeric Molecules

By
Nikolina Mihaylova Orcid logo ,
Nikolina Mihaylova
Andrey Tchorbanov Orcid logo
Andrey Tchorbanov

Abstract

In many physiological processes, peptides play a critical role as neurotrans mitters, hormones, antibiotics, etc. They have research importance in fields such as immunology, pharmacology, neuroscience and cell biology. There are many approaches for immunotherapies: some of them use the peptides as important components of chimeric molecules for immunosuppression, the others - as peptide-based vaccines for immunostimulation. These immunotherapeutic strategies offer the advantages of being safe, easy to produce, devoid of oncogenic potential, and can be chemically or genetically engineered into defined conformational active form. 
The peptides contain very important functional part called epitope, which is recognized by the immune system, specifically by antibodies, B or T cell receptors. Epitopes play a prominent role in the peptide-based vaccines and disease diagnosis. 
Protein-engineered or genetically engineered peptides conjugated to antibody-carrier could be used as a targeting device delivering the epitopes to the cells of interest.  

References

1.
Mackay M, Stanevsky A, Wang T, Aranow C, Li M, Koenig S, et al. Selective dys regulation of the Fc gammaIIB receptor on memory B cells in SLE. J Exp Med. 2006;203:2157–64.
2.
Kang HK, Michaels MA, Berner BR, Datta SK. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol. 2005;174(3247).
3.
Kaliyaperumal A, Michaels MA, Datta SK. Naturally processed chromatin peptides reveal a major autoepitope that primes pathogenic T and B cells of lupus. J Immunol. 2002;168(2530).
4.
Salaman MR, Mawer DPC, Hogarth MB, Seifert MH, Isenberg DA. Counter-proliferative effects of nu cleosomal antigens in cultures from lupus patients. Lupus. 2001;10(332).
5.
Tchorbanov AI, Voynova EN, Mihaylova NM, Todorov TA, Nikolova M, Yomtova VM, et al. Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice. Eur J Immunol. 2007;37:3587–359.
6.
Deocharan B, Qing X, Lichauco J, Putterman C. {Alpha}-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J Immunol. 2002;168:3072–8.
7.
Sun Y, Fong KY, Chung MCM, Yoa ZJ. Peptide mimicking antigenic and immunogenic epitope of double-stranded DNA in systemic lupus erythemato sus. Intern Immunol. 2001;13:223–32.
8.
Putterman C, Deocharan B, Diamond B. Molecular Analysis of the Autoantibody Response in Peptide - Induced Autoimmunity. J Immunol. 2000;164:2542–9.
9.
Putterman C, Diamond B. Immunization with a peptide dsDNA surrogate induces autoantibody pro duction and kidney immunoglobulin deposition. J Exp Med. 1998;188(29).
10.
Gaynor B, Putterman C, Valadon P, Spatz L, Scharff MD, Diamond B. Peptide inhibition of glomerular deposition of an anti-DNA antibody. 13 ACTA FACULTATIS MEDICAE NAISSENSIS. 1997;94(1955).
11.
S. B. Methods in Enzymology. 1980;70:151–9.
12.
Mehod AR, Mant CT, Gera L, Stewart J. Prepara tive reversed-phase liquid chromatography of pepti des. Isocratic tow-step elution system for high loads on analytical coluns. J Chrom A. 2002;972:87–99.
13.
Treves S, Bajocchi G, Zorzato F, Govoni M, Trotta F. Identification and characterization of a calreticulin binding nuclear protein as histone (H1), an autoanti gen in systemic lupus erythematosus. Lupus. 1998;7(479).
14.
Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV. Genetic modifiers of systemic lupus erythemato sus in Fc{gamma}RIIB–/– mice. J Exp Med. 2002;195:1167–74.
15.
Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV. Augmented humoral and anaphylactic responses in Fcgamma RII-deficient mice. Nature. 1996;379:346–9.
16.
Kaneko Y, Nimmerjahn F, Madaio MP, Ravetch JV. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med. 2006;203:789–97.
17.
F. N, JV R. Fcgamma receptors: Old friends and new family members. Immunity. 2006;19–28.
18.
Daeron M, Lesourne R. Negative signaling in Fc receptor complexes. Adv Immunol. 2006;89:39–86.
19.
Voynova EN, Tchorbanov AI, Todorov TA, Vassilev TL. Breaking of tolerance to native DNA in nonauto immune mice by immunization with natural protein/ DNA complexes. Lupus. 2005;14:543–50.
20.
Yachimovich-Cohen N, Fischel R, Bachar N, Yarkoni Y, Eilat D. Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high-affinity anti dsDNA autoantibodies from low-affinity precursors. Eur J Immunol. 2003;33:2469–78.
21.
Radic MZ, Weigert M. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu Rev Immunol. 1994;12:487–520.
22.
Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody, reveals an antibody-indepen dent role for B cells in murine lupus. J Exp Med. 1999;189:1639–48.
23.
Leonard JP, Goldenberg DM. Preclinical and clini cal evaluation of epratuzumab (anti-CD22 IgG) in B cell malignancies. Oncogene. 2007;26:3704–13.
24.
Wan H. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest. 1999;104:123–33.
25.
Nagy Z, Rajnavölgyi E, Hollosi M, Toth GK, Varadi G, Penke B, et al. The intersubunit region of the influenza virus haema gglutinin is recognized by antibodies during infecti on.Scand J Immunol. 1994;40(3):281–91.
26.
Rajnavölgyi E, Horvath A, Gogolak P, Toth KG, Gy F, Fridkin M, et al. Characterizing immu nodominant and protective influenza hemagglutinin epitopes by functional activity and relative binding to 14 Nikolina Mihaylova and Andrey Tchorbanov major histocompatibility complex class II sites. Eur J Immunol. 1997;27:3105–14.
27.
Ivanovska N, Tchorbanov A. Immunization with a DNA chimeric molecule encoding a hemagglutinin peptide and a scFv CD21-specific antibody fragment induces long-lasting IgM and CTL responses to influenza virus. Vaccine. 2006;24:1830–7.
28.
Prechl J, Tchorbanov AI. Targeting of influenza epitopes to murine CR1/CR2 using single-chain anti bodies. Immunopharmacology. 1999;42(1–3):159 65.
29.
Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adju vant: bridging innate and acquired immunity. Science. 1996;271:348–50.
30.
Jozsi M, Prechl J, Bajtay Z, Erdei A. Complement re ceptor type 1 (CD35) mediates inhibitory signals in human B lymphocytes. J Immunol. 2002;168(2782):88.
31.
Duez C. An in vivo model of allergic inflamma tion: pulmonary human cell infiltrate in allergen challenged allergic Hu - SCID mice. Eur J Immunol. 1996;26:1088.
32.
Pestel J. Human IgE in SCID mice reconstituted with peripheral blood mononuclear cells from Derma tophagoides pteronyssinus - sensitive patients. J Immunol. 1994;153:3804.
33.
Jeannin P. Specific histamine release capacity of peptides selected from the modelized Der p I protein, a major allergen of Dermatophagoides ptero nyssinus. Mol Immunol. 1992;29:739.
34.
Duez C. Modulation of the allergen-induced human IgE response in Hu-SCID mice: inhibitory effect of human recombinant IFN-gamma and allergen derived lipopeptide. Europ Cytok Net. 2001;12(3):453–61.
35.
Walker JA, Smith KG. CD22: an inhibitory eni gma. Immunology. 2008;123:314–25.
36.
Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A. A chimeric human-cat fusion protein blocks catinduced allergy. Nat Med. 2005;11(446).
37.
Ewan PW. Allergen immunotherapy. Curr Opin Immu. 1990;1:672.
38.
Yang X, Gieni R, Mosmann TT, Hay Glass KR. Chemi cally modified antigen preferentially elicits induction of Th1-like cytokine synthesis patterns in vivo. J Exp Med. 1993;178:349.
39.
Kalsheker N. The House Dust Mite Allergen Der p1 Catalytically Inactivates a1-Antitrypsin by Specific Reactive Centre Loop Cleavage: A Mechanism that promotes airway inflammation and asthma. Biochem and Biophys Res Com. 1996;221:59–61.
40.
Ball T. B cell epitopes of the major timothy grass pollen allergen, Phl p1, revealed by gene frag mentation as candidates for immunotherapy. FASEB J. 1999;13:1277–90.
41.
Clément M, Rocher J, Loirand G, Le Pendu J. Expression of sialyl-Tn epitopes on beta1 integrin alters epithelial cell phenotype, proliferation and haptotaxis. J Cell Sci. 2004;117:5059–69.
42.
Banerjee S, Robson P, Soutter WP, Foster CS. Modulated expression of glycoprotein oligosaccha rides identifies phenotypic differentiation in squamous carcinomas of the human cervix. Hum Pathol. 1995;26:1005–13.
43.
Samuelsson A, Towers TL, Ravetch JV. Anti-infla mmatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291:484–6.
44.
Weinrich V, Sondermann P, Frey J. Epitope ma pping of new monoclonal antibodies recognizing dis tinct human FcRII (CD32) isoforms. Hybridoma. 1996;15:109–16.
45.
Mihaylova N, Voynova E, Tchorbanov A, Nikolova M, Michova A, Todorov T, et al. Selective silencing of disease-associated B-lymphocytes by chimeric molecules targeting their FcgIIb receptor. International Immunology. 2007;20:165–75.
46.
Casares S, Zong CS, Radu DL, Miller A, Bona CA, Brumeanu TD. Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation. J Exp Med. 1999;190:543–53.
47.
Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalo myelitis by a synthetic polypeptide. Eur J Immunol. 1971;1:242–8.
48.
Ziemssen T, Neuhaus O, Hohlfeld R. Risk-benefit assessment of glatiramer acetate in multiple sclero sis. Drug Saf. 2001;24:979–90.
49.
Offner H, Subramanian S, Wang C, Afentoulis M, Vandenbark AA, Huan J, et al. Treatment of passive experimental autoimmune encephalomye litis in SJL mice with a recombinant TCR ligand indu ces IL-13 and prevents axonal injury. J Immunol. 2005;175:4103–11.
50.
Adamus G, Burrows GG, Vandenbark AA, Offner H. Treatment of autoimmune anterior uveitis with recombinant TCR ligands. Invest Ophthalmol Vis Sci. 2006;47:2555–61.
51.
Karabekian Z, Lytton SD, Silver PB, Sergeev YV, Schneck JP, Caspi RR. Antigen/MHC class II/Ig dimers for the study of uveitogenic T cells: IRBP p161 180 presented by both IA and IE molecules. Invest Ophthalmol Vis Sci. 2005;46:3769–76.
52.
Casares S, Hurtado A, McEvoy RC, Sarukhan A, Boehmer H, Brumeanu TD. Down-regulation of diabetogenic CD4_ T cells by a soluble dimeric pepti de-MHC class II chimera. Nat Immunol. 2002;3:383–91.
53.
Masteller EL, Warner MR, Ferlin W, Judkowski V, Wilson D, Glaichenhaus N, et al. Pep tide-MHC class II dimers as therapeutics to modula te antigen-specific T cell responses in autoimmune diabetes. J Immunol. 2003;171:5587–95.
54.
Zuo L, Cullen CM, DeLay ML, Thornton S, Myers LK, Rosloniec EF, et al. A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsi- veness. J Immunol. 2002;168:2554–9.
55.
Casares S, Bona CA, Brumeanu TD. Engineering and characterization of a murine MHC class II immunoglobulin chimera expressing an immunodo minant CD4 T viral epitope. Protein Eng. 1997;10:1295–301.
56.
Appel H, Seth NP, Gauthier L, Wucherpfennig KW. Anergy induction by dimeric TCR ligands. J Immunol. 2001;166:5279–85.
57.
Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E, et al. A pilot trial of Cop 1 in exacerba ting-remitting multiple sclerosis. N Engl J Med. 1987;317:408–14.
58.
Martinez NR, Augstein P, Moustakas AK, GK P, Gregori S, Adorini L, et al. Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest. 2003;111:1365–71.
59.
Tisch R, Wang B, Serreze DV. Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. J Immunol. 1999;163:1178–87.
60.
MS A, JA B. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23:447–85.
61.
Tisch R, McDevitt HO. Insulin-dependent diabe tes mellitus. Cell. 1996;85:291–7.
62.
Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994;15:516–42.
63.
Fife BT, Guleria I, Gubbels Bupp M, Eagar TN, Tang Q, Bour-Jordan H, et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med. 2006,;203:2737–47.
64.
Jain R, Tartar DM, Gregg RK, Divekar RD, Bell JJ, Lee HH, et al. Innocuous IFNγ induced by adjuvant free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. J Exp Med. 2008;205:207–18.
65.
Tisch R, Wang B, Serreze DV. Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. J Immunol. 1999;163:1178–87.
66.
Bach JF. Immunotherapy of insulin-dependent diabe tes mellitus. Curr Opin Immunol. 2001;13:601–5.
67.
Cava A. Immunotheraphy with peptides in systemic lupus erythematosus. Curr Med Chem. 2009;16:1482–8.
68.
Ohnishi K, Ebling FM, Mitchell B, Singh RR, Hahn BH, Tsao BP. Comparison of pathogenic and non-patho genic murine antibodies to DNA: antigen binding and structural characteristics. Int Immunol. 1994;6(817):30.
69.
Bolland S, Ravetch JV. Spontaneous auto immune disease in Fc(gamma)RIIB-deficient mice results from strainspecific epistasis. Immunity. 2000;13(277).
70.
Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF. Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med. 2006;203:743.
71.
Ravetch JV, Lanier LL. Immune Inhibitory Recep tors. Science. 2000;290:84–9.
72.
Gergely J, Pecht I, Sármay G. Immunoreceptor tyrosine-based inhibition motif-bearing receptors regulate the immunoreceptor tyrosine-based activation motifinduced activation of immune competent cells. Immunol Lett. 1999;68:3–15.
73.
Dörner T. Crossroads of B-cell activation in auto immunity: Rationale of targeting B-cells. J Rheumatol. 2006;33:3–11.
74.
Healy JI, Goodnow CC. Positive versus negativve signalling by B lymphocyte receptors. Ann Rev Immu nol. 1998;16:645–70.
75.
Gold MR. To make antibodies or not: signaling by the B-cell antigen receptor. Trends Pharmacol Sci. 2002;23:316–24.
76.
Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic auto immune disease. Nat Rev Immunol. 2001;1:147 153.
77.
Hahn BH, Singh RR, Wong WK, Tsao BP, Bulpitt K, Ebling FM. Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus. Arthritis Rheum. 2001;44:432–41.
78.
Tsao BP, Ebling FM, Roman C, Panosian-Sahakian N, Calame K, Hahn BH. Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus. J Clin Invest. 1990;85:530–40.
79.
Cava A. Modulation of autoimmunity with artificial peptides. Autoimmunity Reviews. 2010;10:18–21.
80.
Cava A, BH H. Immunotherapy with Ig-derived peptides in SLE: current status and directions. Progress in systemic lupus erythematosus research. 2008;131–53.
81.
Mohan C, Adams S, Stanik V, Datta S. Nucleo some: a major immunogen for pathogenic autoanti body-inducing T cells of lupus. J Exp Med. 1993;177(1367).
82.
Schett G, Smole J, C Z. The auto immune response to chromatin antigens in systemic lupus erythematosus: autoantibodies against hi-stone H1 are a highly specific marker for SLE associated with increased disease activity. Lupus. 2002;11(704).
83.
Kotzin BL. Systemic lupus erythematosus. Cell. 1996;85(303).
84.
Smith CE, Miller SD. Multi-peptide coupled-cell tole rance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities. J Auto immun. 2006;27:218–31.
85.
Zhong MC, Rosbo N, Ben-Nun A. Multianti gen/multiepitopedirected immune-specific suppression 12 Nikolina Mihaylova and Andrey Tchorbanov of “complex autoimmune encephalomyelitis” by a novel protein product of a synthetic gene. J Clin In vest. 2002;110:81–90.
86.
Schrempf W, Ziemssen T. Glatiramer acetate: mecha nisms of action in multiple sclerosis. Autoimmun Rev. 2007;6:469–75.
87.
Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and incre ased IL-10 production through modulation of dendritic cells. J Immunol. 2003;170:4483–8.
88.
Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, et al. Multiple sclerosis: comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci USA. 2000;97:7452–7.
89.
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, doubleblind placebocontrolled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268–76.

Citation

Article metrics

Google scholar: See link

The statements, opinions and data contained in the journal are solely those of the individual authors and contributors and not of the publisher and the editor(s). We stay neutral with regard to jurisdictional claims in published maps and institutional affiliations.