VH Gene Products Allow Specific Communication among Immunologic Cell Sets

  • Robert T. Woodland
  • Harvey Cantor
Part of the Contemporary Topics in Immunobiology book series (CTI, volume 11)


Stimulation of the immune system by foreign materials usually results in the production of antibody. The basis for regulation of the duration, intensity, and amount of antibody is not well understood. The first theories that made sense were based on the demonstration that the Darwinian rules that had been put to elegant experimental tests by Luria and Delbruck also applied to the immune system. These ideas were fairly straightforward, in keeping with what was known about the immune system at that time: antibody responses were thought of as a result of the relative concentrations of antigen and specific antibodies in serum; complexing of antibodies with antigen were thought to mask antigenic determinants and gradually decrease the effective concentration of antigenic stimulation (see Uhr and Moller, 1968). Additional experimental analysis suggested that antigen-antibody complexes might themselves inactivate antibody-secreting lymphocytes (or their immediate precursors) either by altering the molecular configuration of antigen (Diener and Feldmann, 1972) or via a direct effect of the Fc portion of antibodies (Chan and Sinclair, 1971; Murgitta and Vas, 1972). In either case, these models relied upon three basic elements: antibody, antigen, and the antibody-secreting cell.


Memory Cell Helper Cell Myeloma Protein Idiotypic Antibody Idiotypic Determinant 
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  1. Andersson, L. C., Binz, H., and Wigzell, H., 1976, Specific unresponsiveness to transplantation antigens induced by autoimmunization with syngeneic, antigen specific T lymphoclasts, Nature (London) 264: 778.CrossRefGoogle Scholar
  2. Bach, B. A., Greene, M. I., Benacerraf, B., and Nisonoff, A., 1979, Mechanisms of regulation of cell mediated immunity. IV. Azobenzenearsonate-specific suppressor factors bear cross-reactive idiotypic determinants the expression of which is linked to the heavy chain allotype linkage group of genes, J. Exp. Med. 149: 1084.PubMedCrossRefGoogle Scholar
  3. Bangasser, S. A., Kapsalis, A. A., Fraker, P. J., and Nisonoff, A., 1975, Competition for antigen by cell populations having receptors with the same specificity but of different idiotype, J. Immunol. 114: 610.PubMedGoogle Scholar
  4. Binz, H., and Askonas, B. A., 1975, Inhibition of mixed leukocyte culture by anti-idiotypic antibody, Eur. J. Immunol. 5: 618.PubMedCrossRefGoogle Scholar
  5. Binz, H., and Wigzell, H., 1975, Shared idiotypic determinants on B and T lymphocytes reactive against the same antigenic determinants. I. Demonstration of similar or identical idiotypes of IgG molecules and T cell receptors with specificity for the same alloantigens, J. Exp. Med. 142: 197.PubMedCrossRefGoogle Scholar
  6. Binz, H., and Wigzell, H., 1978, Induction of specific immune unresponsiveness with purified mixed leukocyte culture-activated T lymphoblasts as auto-immunogen. III. Proof for the existence of auto anti-idiotypic killer T cells and transfer of suppression to normal syngeneic recipients by T or B lymphocytes, J. Exp. Med. 147: 63.PubMedCrossRefGoogle Scholar
  7. Binz, H., Frischknecht, H., Shen, F. W., and Wigzell, H., 1979, Idiotypic determinants on T cell subpopulations, J. Exp. Med. 149: 910.PubMedCrossRefGoogle Scholar
  8. Black, S. J., Hammerling, G., Berek, C., Rajewsky, K., and Eichmann, K., 1976, Idiotypic analysis of lymphocytes in vitro. I. Specificity and heterogeneity of T and B lymphocytes reactive with anti-idiotypic antibodies, J. Exp. Med. 143: 846.PubMedCrossRefGoogle Scholar
  9. Blomberg, B., Gechler, W. R., and Weigert, M., 1972, Genetics of the antibody response to dextran in mice, Science 177: 178.PubMedCrossRefGoogle Scholar
  10. Bona, C., and Paul, W. E., 1979, Cellular basis of regulation of expression of idiotype. I. T-suppressor cells specific for MOPC460 idiotype regulate the expression of cells secreting anti-trinitrophenyl antibodies bearing 460 idiotype, J. EXP. Med. 149: 592.PubMedCrossRefGoogle Scholar
  11. Bottomly, K., Mathieson, B. J., and Mosier, D. E., 1978, Anti-idiotype induced regulation of helper cell function for the response to phosphorylcholine in adult Balb/c mice, J. Exp. Med. 148: 1216.PubMedCrossRefGoogle Scholar
  12. Brown, J. C., and Rodkey, L. S., 1979, Autoregulation of an antibody response via network-induced auto anti-idiotype, J. Exp. Med. 150: 67.PubMedCrossRefGoogle Scholar
  13. Cancro, M. P., Sigal, N. H., and Klinman, N. R., 1978, Differential expression of an equivalent clonotype among Balb/c and C57B1/6 mice, J. Exp. Med. 147: 1.PubMedCrossRefGoogle Scholar
  14. Cantor, H., and Boyse, E. A., 1976, Regulation of cellular and humoral immune responses by T cell subsets, Cold Spring Harbor Symp. Quant. Biol. 41: 23.CrossRefGoogle Scholar
  15. Cantor, H., Shen, F. W., and Boyse, E. A., 1976, Separation of helper T cells from suppressor T cells expressing different Ly components. II. Activation by antigen: After immunization, antigen specific suppressor and helper activities are mediated by distinct T cell subclasses, J. Exp. Med. 143: 1391.PubMedCrossRefGoogle Scholar
  16. Chan, P. L., and St. C. Sinclair, N. R., 1971, Regulation of the immune response: V. An analysis of the function of the Fc portion of antibody in suppression of an immune response with respect to interaction with components of the lymphoid system, Immunology 21: 967.PubMedGoogle Scholar
  17. Claflin, J. L., and Davie, J. M., 1974, Clonal nature of the immune response to phosphorylcholine. IV. Idiotypic uniformity of binding site associated antigenic determinants among mouse anti-phosphorylcholine antibodies, J. Exp. Med. 140: 673.PubMedCrossRefGoogle Scholar
  18. Claflin, J. L., and Davie, J. M., 1975, Clonal nature of the immune response to phosphorylcholine. V. Cross-idiotypic specificity among heavy chains of murine anti-PC antibodies and PC binding myeloma proteins, J. Exp. Med. 141: 1073.PubMedCrossRefGoogle Scholar
  19. Claflin, J. L., and Rudikoff, S., 1976, Uniformity in a clonal repertoire: A case for a germ-line basis of antibody diversity, Cold Spring Harbor Symp. Quant. Biol. 41: 725.CrossRefGoogle Scholar
  20. Cosenza, H., 1976, Detection of anti-idiotype reactive cells in the response to phosphorylcholine, Eur. J. Immunol. 6: 114.PubMedCrossRefGoogle Scholar
  21. Cosenza, H., Julius, M. H., and Augustin, A. A., 1977, Idiotypes as variable region markers: Analogies between receptors on phosphorylcholine specific T and B lymphocytes, Immunol. Rev. 34: 52.CrossRefGoogle Scholar
  22. Cramer, M., Krawinkel, U., Melchers, I., Imanishi-Kari, T., Ben-Neriah, Y., Givol, D., and Rajewsky, K., 1979, Isolated hapten-binding receptors of sensitized lymphocytes. IV. Expression of immunoglobulin variable regions in (4-hydroxy-3 nitrophenyl) acetyl (NP)-specific receptors isolated from murine B and T lymphocytes, Eur. J. Immunol. 9: 332.PubMedCrossRefGoogle Scholar
  23. Diener, E., and Feldman, M., 1972, Relationship between antigen and antibody-induced suppression of immunity, Transplant. Rev. 8: 76.PubMedGoogle Scholar
  24. Dohl, Y., and Nisonoff, A., 1979, Suppression of idiotype and generation of suppressor T cells with idiotype conjugated thymocytes, J. Exp. Med. 150: 909.CrossRefGoogle Scholar
  25. DuClos, T. W., and Kim, B. S., 1977, Suppressor T cells: Presence in mice rendered tolerant to Ly neonatal treatment with anti-receptor antibody or antigen, J. Immunol. 119: 1769.Google Scholar
  26. Eardley, D. D., Hugenberger, J., McVay-Boudreau, L., Shen, F. W., Gershon, R. K., and Cantor, H., 1978, Immunoregulatory circuits among T cell sets. I. T helper cells induce other T cell sets to exert feedback inhibition, J. Exp. Med. 147: 1106.PubMedCrossRefGoogle Scholar
  27. Eardley, D. D., Shen, F. W., Cantor, H., and Gershon, R. K., 1979, Genetic control of immunoregulatory circuits. Genes linked to the Ig locus govern communication between regulatory T cell sets, J. Exp. Med. 150: 44.PubMedCrossRefGoogle Scholar
  28. Eichmann, K., 1974, Idiotype suppression. 1. Influence of the dose and the effector functions of anti-idiotypic antibody on the production of the idiotype, Eur. J. Immunol. 4: 296.PubMedCrossRefGoogle Scholar
  29. Eichmann, K., 1975, Genetic control of antibody specificity in the mouse, Immunogenetics 2: 491.CrossRefGoogle Scholar
  30. Eichmann, K., and Berek, C., 1973, Mendelian segregation of a mouse antibody idiotype, Eur. J. Immunol. 3: 599.PubMedCrossRefGoogle Scholar
  31. Eichmann, K., and Rajewksy, K., 1975, Induction of T and B cell immunity by antiidiotypic antibody, Eur. J. Immunol. 5: 661.PubMedCrossRefGoogle Scholar
  32. Eichmann, K., Falk, I., and Rajewsky, K., 1978, Recognition of idiotypes in lymphocyte interactions. II. Antigen-independent cooperation between T and B lymphocytes that posess similar and complementary idiotypes, Eur. J. Immunol. 8: 853.PubMedCrossRefGoogle Scholar
  33. Eig, B. M., Ju, S.-T., and Nisonoff, A., 1977, Complete inhibition of the expression of an idiotype by a mechanism of B-cell dominance, J. Exp. Med. 146: 1574.PubMedCrossRefGoogle Scholar
  34. Frischknecht, H., Binz, H., and Wigzell, H., 1978, Induction of specific transplantation immune reactions using anti-idiotypic antibodies, J. Exp. Med. 147: 500.PubMedCrossRefGoogle Scholar
  35. Gearhart, P. J., and Cebra, J. J., 1978, Idiotype sharing by murine strains differing in immunoglobulin allotype, Nature (London) 272: 264.CrossRefGoogle Scholar
  36. Gearhart, P. J., Sigal, N. H., and Klinman, N. R., 1977, The monoclonal antiphosphorylcholine antibody response in several murine strains: Genetic implications of a diverse repertoire, J. Exp. Med. 145: 876.PubMedCrossRefGoogle Scholar
  37. Goidl, E. A., Schrater, A. F., Siskind, G. W., and Thorbecke, J., 1979, Production of autoanti-idiotypic antibody during the normal immune response to TNP-Ficoll. II. Hapten-reversible inhibition of anti-TNP plaque forming cells by immune serum as an assay for auto-anti-idiotypic antibody, J. Exp. Med. 150: 154.PubMedCrossRefGoogle Scholar
  38. Hammerling, G. J., and Eichmann, K., 1976, Expression of la determinants on immunocompetent cells, Eur. J. Immunol. 6: 565.PubMedCrossRefGoogle Scholar
  39. Hart, D. A., Wang, A., Pawlak, L. L., and Nisonoff, A., 1972, Suppression of idiotypic specificities in adult mice by administration of anti-idiotypic antibody, J. Exp. Med. 135: 1293.PubMedCrossRefGoogle Scholar
  40. Herzenberg, L. A., Okumura, K., and Metzler, C. M., 1975, Regulation of immunoglobulin and antibody production by allotype suppressor T cells in mice, Transplant. Rev. 27: 56.Google Scholar
  41. Hetzelberger, D., and Eichmann, K., 1978a, Idiotype suppression. III. Induction of unresponsiveness to sensitization with anti-idiotypic antibody: Identification of the cell types tolerized in high zone and in low zone, suppressor cell-mediated idiotype suppression, Eur. J. Immunol. 8: 839.PubMedCrossRefGoogle Scholar
  42. Hetzelberger, D., and Eichmann, K., 1978b, Recognition of idiotypes in lymphocyte interactions. I. Idiotypic selectivity in the cooperation between T and B lymphocytes, Eur. J. Immunol. 8: 846.PubMedCrossRefGoogle Scholar
  43. Imanishi-Kari, T., Raynavolgyi, E., Takemori, T., Jack, R. S., and Rajewsky, K., 1979, The effect of light chain expression on the inheritance of an idiotype associated with primary anti-(4-hydroxy-3 nitrophenyl) acetyl (NP) antibodies, Eur. J. Immunol. 9: 324.PubMedCrossRefGoogle Scholar
  44. Jack, R. S., Imanishi-Kari, T., and Rajewsky, K., 1977, Idiotypic analysis of the response of C57B1/6 mice to the (4-hydroxy-3 nitrophenyl) acetyl group, Eur. J. Immunol. 7: 559.PubMedCrossRefGoogle Scholar
  45. Janeway, C. A., Jr., Sakato, N., and Eisen, H. N., 1975, Recognition of immunoglobulin idiotypes by thymus derived lymphocytes, Proc. Natl. Acad. Sci. U.S.A. 72: 2357.PubMedCrossRefGoogle Scholar
  46. Jerne, N. K., 1974, Towards a network theory of the immune system, Ann. Immunol. (Inst. Pasteur) 125C: 373.Google Scholar
  47. Jorgensen, T., and Hannestad, K., 1977, Specificity of T and B lymphocytes for myeloma protein 315, Eur. J. Immunol. 1: 426.CrossRefGoogle Scholar
  48. Ju, S.-T., Kipps, T. J., Theze, J., Benacerraf, B., and Dorf, M. E., 1978, Idiotypic analysis of anti-GAT antibodies. I. Presence of common idiotypic specificities in both responder and nonresponder mice, J. Immunol. 121: 1034.PubMedGoogle Scholar
  49. Julius, M. H., Cosenza, H., and Augustin, A. A., 1978, Evidence for the endogenous production of T cell receptors bearing idiotypic determinants, Eur. J. Immunol. 8: 484.PubMedCrossRefGoogle Scholar
  50. Karol, R., Reichlin, M., and Noble, R. W., 1978, Idiotypic cross reactivity between antibodies of different specificities, J. Exp. Med. 148: 1488.PubMedCrossRefGoogle Scholar
  51. Kelsoe, G., and Cerny, J., 1979, Reciprocal expansions of idiotypic and anti-idiotypic clones following antigen stimulation, Nature (London) 279: 333.CrossRefGoogle Scholar
  52. Kim, B. S., 1979, Mechanism of idiotype suppression. I. In vitro generation of idiotypespecific suppressor T cells by anti-idiotypic antibodies and specific antigen, J. Exp. Med. 149: 1371.PubMedCrossRefGoogle Scholar
  53. Klaus, G. G. B., 1978, Antigen-antibody complexes elicit anti-idiotypic antibodies to self idiotypes, Nature (London) 272: 265.CrossRefGoogle Scholar
  54. Kluskens, L., and Kohler, H., 1974, Regulation of the immune response by autologous antibody against receptor, Proc. Nat. Acad. Sci. U.S.A. 71: 5083.CrossRefGoogle Scholar
  55. Kohler, H., Richardson, B. C., Rowley, D. A., and Smyk, S., 1977, Immune response to phosphorylcholine. III. Requirement for the Fc portion and equal effectiveness of IgG subclasses in anti-receptor antibody induced suppression, J. Immunol. 119: 1979.Google Scholar
  56. Kohler, H., Richardson, B. C., and Smyk, S., 1978, Immune response to phosphorylcholine. IV. Comparison of homologous and isologous anti-idiotypic antibody, J. Immunol. 120: 232.Google Scholar
  57. Krammer, P. H., and Eichmann, K., 1977, T cell receptor idiotypes are controlled by genes in the heavy chain linkage group and the major histocompatibility complex, Nature (London) 270: 733.CrossRefGoogle Scholar
  58. Krawinkel, U., Cramer, M., Berek, C., Hammerling, G., Black, S. J., Rajewsky, K., and Eichmann, K., 1976, On the structure of the T cell receptor for antigen, Cold Spring Harbor Symp. Quant. Biol. 41: 285.CrossRefGoogle Scholar
  59. Laskin, J. A., Gray, A., Nisonoff, A., Klinman, N. R., and Gottleib, P. O., 1977, Segregation at a locus determining an immunoglobulin genetic marker for the light chain variable region affects inheritance of expression of an idiotype, Proc. Nat. Acad. Sci. U.S.A. 74: 4600.CrossRefGoogle Scholar
  60. Lewis, G. K., and Goodman, J. W., 1978, Purification of functional, determinant-specific idiotype-bearing murine T cell, J. Exp. Med. 148: 915.PubMedCrossRefGoogle Scholar
  61. Lieberman, R., Potter, M., Mushinski, E. B., Humphrey, W., Jr., and Rudikoff, S., 1974, Genetics of a new Ig VH (T15 idiotype) marker in the mouse regulating natural antibody to phosphorylcholine, J. Exp. Med. 139: 983.PubMedCrossRefGoogle Scholar
  62. Lynch, R. G., Graff, R. J., Sirisinha, S., Simms, E. S., and Eisen, H. N., 1972, Myeloma proteins as tumor specific transplantation antigens, Proc. Natl. Acad. Sci. U.S.A. 69: 1540.PubMedCrossRefGoogle Scholar
  63. McKearn, T. J., 1974, Antireceptor antiserum causes specific inhibition of reactivity to rat histocompatibility antigens, Science 183: 94.PubMedCrossRefGoogle Scholar
  64. McKearn, T. J., Stuart, F. P., and Fitch, F. W., 1974, Anti-idiotypic antibody in rat transplantation immunity. I. Production of anti-idiotypic antibody in animals repeatedly immunized with alloantigens, J. Immunol. 113: 1876.PubMedGoogle Scholar
  65. Murgita, R. A., and Vas, S. I., 1972, Specific antibody-mediated effect in the immune response. Suppression and augmentation of the primary immune response in mice by different classes of antibodies, Immunology 22: 319.PubMedGoogle Scholar
  66. Nisonoff, A., Ju, S.-T., and Owen, F. L., 1977, Studies of structure and immunosuppression of a cross reactive idiotype in Strain A mice, Transplant. Rev. 34: 89.Google Scholar
  67. Owen, F. L., Ju, S.-T., and Nisonoff, A., 1977, Presence on idiotype-specific suppressor T cells of receptors that interact with molecules bearing the idiotype, J. Exp. Med. 145: 1559.PubMedCrossRefGoogle Scholar
  68. Parker, D. C., Fothergill, J. J., and Wadsworth, D. C., 1979, B lymphocyte activation by insoluble anti-immunoglobulin: Induction of immunoglobulin secretion by a T cell dependent soluble factor, J. Immunol. 123: 931.PubMedGoogle Scholar
  69. Pawlak, L. L., Mushinski, E. B., Nisonoff, A., and Potter, M., 1973a, Evidence for the linkage of the Ig CH locus to a gene controlling the idiotype specificity of anti-p-azophenylarsonate antibodies in strain A mice, J. Exp. Med. 137: 22.PubMedCrossRefGoogle Scholar
  70. Pawlak, L. L., Hart, D. A., and Nisonoff, A., 1973b, Requirements for prolonged suppression of an idiotypic specificity in adult mice, J. Exp. Med. 137: 1442.PubMedCrossRefGoogle Scholar
  71. Riblet, R., Weigert, M., and Makela, O., 1975, Genetics of mouse antibodies. II. Recombination between VH genes and allotype, Eur. J. Immunol. 5: 778.PubMedCrossRefGoogle Scholar
  72. Riesen, W. F., 1979, Idiotypic cross-reactivity of human and murine phosphorylcholinebinding immunoglobulins, Eur. J. Immunol. 9: 421.PubMedCrossRefGoogle Scholar
  73. Rodkey, L. S., 1974, Studies of idiotypic antibodies: Production and characterization of autoantiidiotypic antisera, J. Exp. Med. 139: 712.PubMedCrossRefGoogle Scholar
  74. Rohrer, J. W., Odermatt, B., and Lynch, R. G., 1979, Immunoregulation of murine myeloma: Isologous immunization with M315 induces idiotype-specific T cells that suppress IgA secretion by MOPC-315 cells in vivo, J. Immunol. 122: 2011.Google Scholar
  75. Sachs, D. H., Berzofsky, J. A., Fathman, C. G., Pisetsky, D. S., Schechter, A. N., and Schwartz, R. H., 1976, The immune response to Staphlococcal nuclease: A probe of cellular and humoral antigen-specific receptors, Cold Spring Harbor Symp. Quant. Biol. 41: 295.CrossRefGoogle Scholar
  76. Sakato, N., Janeway, C. A., and Eisen, H. N., 1976, Immune responses of Balb/c mice to the idiotype of T15 and of other myeloma proteins of Balb/c origin: Implications for an immune network and antibody multispecificity, Cold Spring Harbor Symp. Quant. Biol. 41: 719.CrossRefGoogle Scholar
  77. Schrater, A. F., Goidl, E. A., Thorbecke, J., and Siskind, G. W., 1979, Production of autoanti-idiotypic antibody during the normal immune response to TNP-Ficoll. I. Occurence in AKR/J and Balb/c mice of hapten-augmentable, anti-TNP plaque forming cells and their accelerated appearance in recipients of immune spleen cells, J. Exp. Med. 150: 138.PubMedCrossRefGoogle Scholar
  78. Schuler, W., Weiler, E., and Kolb, H., 1977, Characterization of syngeneic anti-idiotypic antibody against the idiotype of Balb/c myeloma protein J558, Eur. J. Immunol. 7: 649.PubMedCrossRefGoogle Scholar
  79. Seppala, I. J. T., and Eichmann, K., 1979, Induction and characterization of isogenic antiidiotypic antibodies to Balb/c myeloma S117: Lack of reactivity with major idiotypic determinants, Eur. J. Immunol. 9: 243.PubMedCrossRefGoogle Scholar
  80. Sirisinha, S., and Eisen, H. N., 1971, Autoimmune-like antibodies to the ligand-binding sites of myeloma proteins, Proc. Natl. Acad. Sci. U.S.A. 68: 3130.PubMedCrossRefGoogle Scholar
  81. Strayer, D. S., Lee, W. M. F., Rowley, D. A., and Kohler, H., 1975, Anti-receptor antibody. II. Induction of long term unresponsiveness in neonatal mice, J. Immunol. 114: 728.PubMedGoogle Scholar
  82. Tada, T., Taniguchi, M., and David, C. S., 1976, Suppressive and enhancing T cell factors as I region gene products: Properties and the subregion assignment, Cold Spring Harbor Symp. Quant. Biol. 41: 119.CrossRefGoogle Scholar
  83. Tasiaux, N., Leuwenkroon, R., Bruyno, C., and Urbain, J., 1978, Possible occurrence and meaning of lymphocytes bearing auto-anti-idiotypic receptors during the immune response, Eur. J. Immunol. 8: 464.PubMedCrossRefGoogle Scholar
  84. Trenkner, E., and Riblet, R., 1975, Induction of antiphosphorylcholine antibody formation by anti-idiotypic antibody, J. Exp. Med. 142: 1121.PubMedCrossRefGoogle Scholar
  85. Uhr, J. W., and Moller, G., 1968, Regulatory effect of antibody on the immune response, Adv. Immunol 8: 81.PubMedCrossRefGoogle Scholar
  86. Ward, K., Cantor, H., and Boyse, E. A., 1977, Clonally restricted interactions among T and B cell subclasses, in: Regulatory Genetics of the Immune System ( F. Fox, ed.), Academic Press, New York.Google Scholar
  87. Ward, K., Cantor, H., and Nisonoff, A., 1978, Analysis of the cellular basis of idiotypespecific suppression, J. Immunol. 120: 2016.PubMedGoogle Scholar
  88. Weiler, I. J., Weiler, E., Sprenger, R., and Cosenza, H., 1977, Idiotype suppression by maternal influence, Eur. J. Immunol. 1: 591.CrossRefGoogle Scholar
  89. Woodland, R., and Cantor, H., 1978, Idiotype specific T helper cells are required to induce idiotype-positive B memory cells to secrete antibody, Eur. J. Immunol. 8: 600.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • Robert T. Woodland
    • 1
  • Harvey Cantor
    • 2
  1. 1.Department of MicrobiologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Farber Cancer InstituteHarvard Medical SchoolBostonUSA

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