Central European Journal of Biology

, Volume 1, Issue 1, pp 16–28

Mouse model for analysis of non-MHC genes that influence allogeneic response: recombinant congenic strains of OcB/Dem series that carry identical H2 locus

  • Helena Havelková
  • Vladimír Holáň
  • Igor Kárník
  • Marie Lipoldová
Research Article


Alloreactivity is the strongest known primary immune response. Its clinical manifestations are graft rejection, graft-versus-host disease and graft-versus-leukemia effect. The strongest stimulation by allogeneic cells is due to incompatibility at the major histocompatibility complex (MHC) genes. However, the non-MHC genes also participate in allogeneic response. Here we present a mouse model for study of the role of non-MHC genes in regulation of alloreactivity and show that they besides encoding antigens also regulate the responsiveness. Recombinant congenic strains (RCS) of O20/A (O20)-c-B10.O20/Dem (OcB/Dem) series have been derived from the parental strains O20 and B10.O20, which carry identical MHC haplotypes (H2pz) and therefore their differences in alloantigen response depend only on non-MHC genes. We have tested a MLR response by spleen cells of the strains O20, B10.O20, and 16 OcB/Dem strains through stimulation by cells from strains C57BL/10 (H2b), BALB/c (H2d), CBA (H2k), and DBA/1 (H2q) alloantigens. Proliferative response of O20, B10.O20 and OcB/Dem strains to these four alloantigens exhibited a similar but not completely identical pattern of reactivity. The responses to different alloantigens were highly correlated: C57BL/10-BALB/c r = 0.87, C57BL/10-CBA r = 0.84, C57BL/10-DBA/1 r = 0.83. Cluster analysis of the responses by O20, B10.O20, and OcB mice identified groups of strains with distinct patterns of response. This data shows that two main types of genes influence MLR: 1. structural genes for major and minor alloantigens and 2. genes regulating T-cell receptor signal transduction or mediating costimulatory signals by antigen-presenting cells.


Alloresponse non-MHC genes mouse genetic model mixed lymphocyte response recombinant congenic strains 







major histocompatibility complex


mixed lymphocyte response


mixed lymphocyte culture


recombinant congenic strains


transforming growth factor


tumor necrosis factor


quantitative trait loci


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    S. Friedman, D. Sillcocks and H. Cantor: “Alloreactivity of an OVA-specific T-cell clone. I. Stimulation by class II MHC and novel non-MHC B-cell determinants”, Immunogenetics, Vol. 26, (1987), pp. 193–203.PubMedCrossRefGoogle Scholar
  2. [2]
    T.E. Starzl, T.L. Marchioro, J.H. Holmes, G. Hermann, R.S. Brittain, O.H. Stonington, D.W. Talmage and W.R. Waddell: “Renal homografts in patients with major donor-recipient blood group incompatibilities”, Surgery, Vol. 55, (1964), pp. 195–200.PubMedGoogle Scholar
  3. [3]
    V. Lenhard, B. Hansen, D. Roelcke, K. Dreikorn, P. Wernet, H. Bockhorn, W. Fassbinder, R.F. Fetta, H. Wilms, B. Gumbel, F.W. Albert, R.W. Ewald, I. Sprenger-Klasen and S.F. Goldmann: “Influence of Lewis and other blood group systems in kidney transplantation”, Proc. Eur. Dial. Transplant. Assoc., Vol. 19, (1983), pp. 432–437.PubMedGoogle Scholar
  4. [4]
    J.C. Gluckman, C. Foucault, H. Beaufils, J. Luciani, J. Cartron and P.F. Frantz: “Rh antibodies after kidney transplantation”, Transplantation, Vol. 32, (1981), pp. 260–262.PubMedCrossRefGoogle Scholar
  5. [5]
    E. Spierings, B. Wieles and E. Goulmy: “Minor histocompatibility antigens—big in tumour therapy”, Trends Immunol. Vol. 25, (2004), pp. 56–60.PubMedCrossRefGoogle Scholar
  6. [6]
    A.J. Barrett, K. Rezvani, S. Solomon, A.M. Dickinson, X.N. Wang, G. Stark, H. Cullup, M. Jarvis, P.G. Middleton and N. Chao: “New developments in allotransplant immunology”, Hematology (Am. Soc. Hematol. Educ. Program), (2003), pp. 350-371.Google Scholar
  7. [7]
    S.M. Katz, M. Liebert, T. J. Gill III, H.W. Kunz, D.V. Cramer and R.D. Guttmann: “The relative roles of MHC and non-MHC genes in heart and skin allograft survival”, Transplantation, Vol. 36, (1983), pp. 96–101.PubMedGoogle Scholar
  8. [8]
    A.R. Youssef, C. Otley, P.W. Mathieson and R.M. Smith: “Role of CD4+ and CD8+ T cells in murine skin and heart allograft rejection across different antigenic desparities”, Transpl. Immunol., Vol. 13, (2004), pp. 297–304.PubMedCrossRefGoogle Scholar
  9. [9]
    Z. Haskova, T.J. Sproule, D.C. Roopenian and A.B. Ksander: “An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection”, Transplantation, Vol. 75, (2003), pp. 1368–1374.PubMedCrossRefGoogle Scholar
  10. [10]
    K. Rao, R.D. Lund, H.W. Kunz and T.J. Gill III: “The role of MHC and non-MHC antigens in the rejection of intracerebral allogeneic neural grafts”, Transplantation, Vol. 48, (1989), pp. 1018–1021.PubMedGoogle Scholar
  11. [11]
    B. Korngold and J. Sprent: “Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow”, J. Exp. Med., Vol. 148, (1978), pp. 1687–1698.PubMedCrossRefGoogle Scholar
  12. [12]
    C.S. Via and G.M. Shearer: “T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease”, Immunol. Today, Vol. 9, (1988), pp. 207–213.PubMedCrossRefGoogle Scholar
  13. [13]
    I. Miconnet, T. Roger, M. Seman and M. Bruley-Rosset: “Critical role of endogenous Mtv in acute lethal graft-versus-host disease”, Eur. J. Immunol., Vol. 25, (1995), pp. 364–368.PubMedGoogle Scholar
  14. [14]
    S.C. Muluk, F.T. Hakim and G.M. Shearer: “Regulation of graft-versus-host reaction by Mlsa-reactive donor T cells”, Eur. J. Immunol., Vol. 22, (1992), pp. 1967–1973.PubMedGoogle Scholar
  15. [15]
    R.A. Mann, A.B. Singh, M. Singh and A.E. Jetzt: “The host response in graft-versus-host disease. II. The emergence of host protective cells is in part determined by background genomic compatibility”, Cell. Immunol., Vol. 151, (1993), pp. 39–51.PubMedCrossRefGoogle Scholar
  16. [16]
    H. Havelková, J. Badalová, P. Demant and M. Lipoldová: “A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA”, Genes Immun., Vol. 1, (2000), pp. 483–487.PubMedCrossRefGoogle Scholar
  17. [17]
    V. Holáň, H. Havelková, M. Krulová, P. Demant and M. Lipoldová: “A novel alloreactivity controlling locus, Alan1 mapped to mouse chromosome 17”, Immunogenetics, Vol. 51, (2000), pp. 755–757.PubMedCrossRefGoogle Scholar
  18. [18]
    R.D. Allen, J.A. Dobkins, J.M. Harper and D.L. Slayback: “Genetics of graft-versus-host disease, I. A locus on chromosome 1 influences development of acute graft-versus-host disease in a major histocompatibility complex mismatched murine model”, Immunology, Vol. 96, (1999), pp. 254–261.PubMedCrossRefGoogle Scholar
  19. [19]
    L.D. Fast: “Identification of a single non-H2 gene regulating graft-versus-host disease response”, J. Immunol., Vol. 144 (1990), pp. 4177–4182.PubMedGoogle Scholar
  20. [20]
    J.M. Harper, D.L. Slayback, J.A. Dobkins and R.D. Allen: “A locus on chromosome 2 influences the development of acute graft-versus-host disease in a murine model”, Bone Marrow Transplant., Vol. 23, (1999), pp. 1183–1190.PubMedCrossRefGoogle Scholar
  21. [21]
    D.L. Slayback, J.A. Dobkins, J.M. Harper and R.D. Allen: “Genetic factors influencing the development of chronic graft-versus-host disease in a murine model”, Bone Marrow Transplant., Vol. 26, (2000), pp. 931–938.PubMedCrossRefGoogle Scholar
  22. [22]
    M. Rychlíková, P. Demant and P. Ivanyi: “The mixed lymphocyte reaction in H2K, H2D, and non-H2 incompatibility”, Biomedicine, Vol. 18, (1973), pp. 401–407.PubMedGoogle Scholar
  23. [23]
    M. Berger, P.J. Wettstein and R. Korngold: “T cell subsets involved in lethal graft-versus-host disease directed to immunodominant minor histocompatibility antigens”, Transplantation, Vol. 57, (1994), pp. 1095–1102.PubMedGoogle Scholar
  24. [24]
    M.A. Williams, J. Trambley, J. Ha, A.B. Adams, M.M. Durham, P. Rees, S.R. Cowan, T.C. Pearson and C.P. Larsen: “Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts”, J. Immunol., Vol. 165, (2000), pp. 6849–6857.PubMedGoogle Scholar
  25. [25]
    P. Demant and A.A.M. Hart: “Recombinant congenic strains: a new tool for analyzing genetic traits determined by more than one gene”, Immunogenetics, Vol. 24, (1986), pp. 416–422.PubMedCrossRefGoogle Scholar
  26. [26]
    M. Lipoldová, M. Kosařová, A. Zajícová, V. Holáň, A.A.M. Hart, M. Krulová and P. Demant: “Separation of multiple genes controlling the T cell proliferative response to IL-2 and anti-CD3 using Recombinant Congenic Strains”, Immunogenetics, Vol. 41, (1995), pp. 301–311.PubMedCrossRefGoogle Scholar
  27. [27]
    M. Kosařová, H. Havelková, M. Krulová, P. Demant and M. Lipoldová: “The production of two Th2 cytokines, interleukin-4 and interleukin-10, is controlled independently by locus Cypr1 and by loci Cypr2 and Cypr3 respectively”, Immunogenetics, Vol. 49, (1999), pp. 134–141.PubMedCrossRefGoogle Scholar
  28. [28]
    H. Havelková, M. Kosařová, M. Krulová, P. Demant and M. Lipoldová: “T-cell proliferative response is controlled by loci Tria4 and Tria5 on mouse chromosomes 7 and 9”, Mamm. Genome, Vol. 10, (1999), pp. 670–674.PubMedCrossRefGoogle Scholar
  29. [29]
    M. Lipoldová, H. Havelková, J. Badalová and P. Demant: “Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function, and lung tumor susceptibility”, Int. J. Cancer, Vol. 114, (2005), pp. 394–399.PubMedCrossRefGoogle Scholar
  30. [30]
    R.J. Fijneman, M. Vos, J. Berkhof, P. Demant and G. Kraal: “Genetic analysis of macrophage characteristics as a tool to identify tumor susceptibility genes: mapping of three macrophage-associated risk inflammatory factors, marif1, marif2, and marif3”, Cancer Res., Vol. 64, (2004), pp. 3458–3464.PubMedCrossRefGoogle Scholar
  31. [31]
    G.E. Franco, S.J. Litscher, T.K. O’Neil, M. Piette, P. Demant and R.D. Blank: “Dual energy X ray absorptiometry of ex vivo HcB/Dem mouse long bones: left are denser than right”, Calcif. Tissue Int., Vol. 76, (2005) pp. 26–31.PubMedCrossRefGoogle Scholar
  32. [32]
    V.V. Colinayo, J.H. Qiao, P. Demant, K. Krass, A.J. Lusis and T.A. Drake: “Genetic characterization of the Dyscalc locus”, Mamm. Genome, Vol. 13, (2002), pp. 283–288.PubMedCrossRefGoogle Scholar
  33. [33]
    P. Demant, M. Lipoldová and M. Svobodová: “Resistance to Leishmania major in mice”, Science, Vol. 274, (1996), pp. 1392–1393.PubMedCrossRefGoogle Scholar
  34. [34]
    M. Lipoldová, M. Svobodová, M. Krulová, H. Havelková, J. Badalová, E. Nohýnková, V. Holáň, A.A.M. Hart, P. Volf and P. Demant: “Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes”, Genes Immun., Vol. 1, (2000), pp. 200–206.PubMedCrossRefGoogle Scholar
  35. [35]
    M. Lipoldová, M. Svobodová, H. Havelková, M. Krulová, J. Badalová, E. Nohýnková, A.A.M. Hart, D. Schlegel, P. Volf and P. Demant: “Mouse genetic model for clinical and immunological heterogeneity of leishmaniasis”, Immunogenetics, Vol. 54, (2002), pp. 174–183.PubMedCrossRefGoogle Scholar
  36. [36]
    V. Vladimirov, J. Badalová, M. Svobodová, H. Havelková, A.A.M. Hart, H. Blažková, P. Demant and M. Lipoldová: “Different genetic control of cutaneous and visceral disease after Leishmania major infection in mouse”, Infect. Immun., Vol. 71, (2003), pp. 2041–2046.PubMedCrossRefGoogle Scholar
  37. [37]
    R.J.A. Fijneman, S.S. de Vries, R.C. Jansen and P. Demant: “Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3 and Sluc4 that influence susceptibility to lung cancer in the mouse”, Nature Genet., Vol. 14, (1996), pp. 465–467.PubMedCrossRefGoogle Scholar
  38. [38]
    T. van Wezel, A.P. Stassen, C.J. Moen, A.A.M. Hart, M.A. van der Valk and P. Demant: “Gene interaction and single gene effects in colon tumour susceptibility in mice”, Nat. Genet., Vol. 14, (1996), pp. 468–470.PubMedCrossRefGoogle Scholar
  39. [39]
    P. Demant: “Cancer susceptibility in the mouse: genetics, biology and implications for human cancer”, Nat. Rev. Genet., Vol. 4, (2003), pp. 721–734.PubMedCrossRefGoogle Scholar
  40. [40]
    J.S. Bodnar, A. Chatterjee, L.W. Castellani, D.A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K.M. Dains, J. Catanese, M. Chu, S.S. Sheth, K. Charugundla, P. Demant, D.B. West, P. de Jong and A.J. Lusis: “Positional cloning of the combined hyperlipidemia gene Hyplip1”, Nat. Genet., Vol. 30, (2002), pp. 110–116.PubMedCrossRefGoogle Scholar
  41. [41]
    A.J. Van Oosterhout, P.V. Jeurink, P.C. Groot, G.A. Hofman, F.P. Nijkamp and P. Demant: “Genetic analysis of antigen-induced airway manifestations of asthma using recombinant congenic mouse strains”, Chest, Vol. 121, (2002) p. 13S.PubMedCrossRefGoogle Scholar
  42. [42]
    V. Holáň, M. Lipoldová and P. Demant: “Identical genetic control of MLC reactivity to different MHC incompatibilities, independent of production and response to IL-2”, Immunogenetics, Vol. 44, (1996), pp. 27–35.PubMedCrossRefGoogle Scholar
  43. [43]
    A. Czarnomska and P. Demant: “H-2 antigenic specificities controlled by the translocation chromosome T190”, Transplantation, Vol. 30, (1980), pp. 69–72.PubMedGoogle Scholar
  44. [44]
    J. Klein: “Immunologically important loci”, In: M. Lyon and A.G. Searle (eds.): Genetic variants and strains of the laboratory mouse, 2nd ed., Oxford University Press, Oxford, 1989, pp. 797–825.Google Scholar
  45. [45]
    A.P.M. Stassen, P.C. Groot, J.T. Eppig and P. Demant: “Genetic composition of the recombinant congenic strains” Mamm. Genome, Vol. 7, (1996), pp. 55–58.PubMedCrossRefGoogle Scholar
  46. [46]
    J.H. Ward: “Hierarchical Grouping to Optimize an Objective Function”, J. Am. Stat. Assoc., Vol. 58, (1963), pp. 236–244.CrossRefGoogle Scholar
  47. [47]
    J.A. Hartigan: Clustering algorithms, J. Wiley, New York, 1975.Google Scholar
  48. [48]
    R.J. Fijneman, M.A. van der Valk and P. Demant: “Genetics of quantitative and qualitative aspects of lung tumorigenesis in the mouse: multiple interacting Susceptibility to lung cancer (Sluc) genes with large effects”, Exp. Lung Res., Vol. 24, (1998), pp. 419–436.PubMedCrossRefGoogle Scholar

Copyright information

© Central European Science Journals Warsaw and Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Helena Havelková
    • 1
  • Vladimír Holáň
    • 1
  • Igor Kárník
    • 1
  • Marie Lipoldová
    • 1
  1. 1.Institute of Molecular GeneticsAcademy of Sciences of the Czech RepublicPragueCzech Republic

Personalised recommendations