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Ageing and genetic control of immune responsiveness
Immunology Letters, 40 (1994) 231-233 Elsevier Science B.V. IMLET 02145
Ageing and genetic control of immune responsiveness Gino Doria* and Daniela Frasca Laboratory of lmmunology, AMB-EFF, ENEA Casaccia, 00060 S. Maria Galeria, Rome, Italy (Accepted 29 January 1994)
1.
Summary
Ageing is associated with a progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena [1,2]. Many studies have been focussed on the mechanisms of the immunologic features of ageing. Alterations in cellular components of the immune system rather than in the extracellular milieu seem to account for most of the variations of immune competence in ageing [3].
2. Introduction
The decrease in immune reactivity with increasing age may reflect multiple events, affecting cell proliferation and differentiation, leading to reduction in cell number and function within one or more cell populations [4]. Limiting dilution analysis of immune competent T cells indicates that the frequency of responding cells declines with ageing but the progeny of each cell maintains full proliferative capacity and immune competence [5]. These age-related changes in the T-cell population are not clearly connected with modifications of the CD4+/CD8 ÷ cell ratio but seem to reflect a shift from CD45RA + to CD45RO ÷ cell subsets, entailing a decreased sensitivity to mitogens and a reduction in both IL-2 production and IL-2R expression [6]. The decline in Tcell immune responsiveness to exogenous antigens has been attributed to thymus involution consisting
Key words: Exogenous antigen; Autoimmunity; Interleukin-2; Cell proliferation; Cell differentiation; Thymus *Corresponding author: Dr. G. Doria, Laboratory of Immunology, AMB-EFF, ENEA Casaccia, Via Anguillarese 301, 00060 S. Maria Galeria, Rome, Italy. Tel.: + 39 6 30483619; Fax: + 39 6 30483644. SSDI 0 1 6 5 - 2 4 7 8 ( 9 4 ) 0 0 0 6 1 - U
of a fall in the capacity to induce intrathymic T-cell growth and differentiation [7]. Alterations of the intrathymic environment may be bound to reduced expression of MHC molecules on epithelial cells [8] and decreased production and secretion of thymic hormones [9] and cytokines [10]. Also ageing of bone marrow stem cells may contribute to thymus involution as they display reduced potential to differentiate into T cells upon transfer from old donors to young thymic environment [11]. The increasing incidence of autoimmunity in ageing is difficult to reconcile with the progressive immunodeficiency to exogenous antigens. Beside the intrinsic B-cell resistance to tolerance induction in ageing [12], the concomitant appearance of autoreactive T cells [13,14] has suggested that the mechanisms of the development and maintenance of self-tolerance deteriorate with ageing. Age-related accumulation of thymic stromal damage may, indeed, hamper negative selection leading to ineffective elimination of autoreactive T-cell clones. Furthermore, ageing may also affect the peripheral mechanisms of tolerance induction by reducing cell sensitivity to clonal anergy, cell production of inhibitory lymphokines, or anti-idiotype cell reactivity against self-antigen receptors [15].
3. Immune responsiveness in senescence
Therapeutic intervention in ageing is a difficult task as it requires very accurate protocols to reach the antithetic objectives of correcting immune defects and mitigating autoreactivity. Restoration of immune responsiveness in old individuals was achieved by hormone administration [16-20] and by other treatments [21,22]. In one [19] of these studies, T helper cell activity was found to have increased in old mice shortly after the injection of a single dose of
TABLE 1 EFFECT OF THYMIC HORMONES ON TH CELL ACTIVITY IN OLD MICE Synthetic thymic hormones
Doubling dose ng*
Thymic humoral factor (THF-72) Thymopentin (TP5) Thymosin-ctl (Thy-al)
Relative efficiency
0.17 (2.45) 6,67 (1.87) 229.55 (1.56)
Weight
Molarity
1350 34 1
414 8 1
THF-72:8 aa, MW 954; TP5:5 aa, MW 776; Thy-ah 28 aa, MW 3110. *Error factor by which the dose should be multiplied or divided to obtain the variation due to one S.E.
synthetic thymosin-al (Thy-al), thymopentin (TP5), or thymic humoral factor (THF-72). The relative efficacy of these thymic hormones was assessed over a wide dose range and it was found that THF-72 and TP5 were 400-fold and 8-fold more effective than Thy-~l, respectively (Table 1). Immunorestoration, however, suffers the risk of increasing autoreactivity as well. Thus, careful clinical examination should aim at a risk/benefit evaluation before any immunorestorative intervention. It should be pointed out that it is unclear what should be the optimal level of immune responsiveness in senescence to maintain or prolong the life span and improve the biological quality of life. A genetic approach to this issue indicated that high immune responsiveness is positively correlated with life span and resistance to cancer and other illnesses [23]. Mice of a genetically heterogeneous population were selected (Selection II) for high (H) or low (L) agglutinin response to sheep red blood cells (SRBC) for 39 generations. Thereafter, the parental line (H and L), cross (F1), intercross (F2), and backcross (BcH and BcL) progenies were immunized with SRBC, tested for the agglutinin response, and then followed until spontaneous death to detect tumors and inflammatory diseases. Genetic analysis of the result of Selection II indicated that immune responsiveness is a
quantitative trait under polygenic control as it is regulated by 5-7 independent loci. Selection and segregation of this set of genes affect not only the agglutinin response to SRBC but also immune responses to other immunogens unrelated to the selection antigen [24]. Table 2 shows that the higher agglutinin titer is correlated with longevity and low incidence of lymphomas, solid tumors, and chronic nephritis. Pleiotropic action of the same genes or linkage of different genes that control these characters may explain why selection and segregation of immune responsiveness bring about concomitant changes in the other characters. The data, however, are also compatible with the possibility that it is the immune system, rather than the selected genes, that directly influences life span and disease incidence. The hypothesis of a determinant role of the immune system would receive further support if the life span of L mice could be extended by manipulations that enhance their immune performance. This issue is presently being investigated in our laboratory.
4. Conclusion
In conclusion, this immunologic approach to ageing may lead to the possibility of increasing immune
TABLE 2 IMMUNE RESPONSE, LIFE SPAN, AND MORBIDITY IN MICE FROM SELECTION II Mouse population
H L FI F2 BcH BcL
No. of mice
134 123 153 192 174 102
Agglutinin log2 titer (mean ± SD)
11.4 ± 0.8
5.2 9.4 9.8 10.8 7.5
*Age-adjusted percentage.
232
___ 1.0 ± 0.7 ± 1.2 ± 0.9 ± 1.4
Life span (days)
Disease incidence*
Total population (mean ± SD)
Last 20% survivors (mean ± SD)
Lymphomas
Solid tumours
Chronic nephritis
612 346 549 513 530 464
752 444 747 681 748 608
14 62 45 32 40 40
27 45 38 38 30 36
18 70 12 19 9 52
± ± ± ± ± ±
148 110 186 183 215 158
± 64 ± 74 ± 62 ± 85 ± 71 ± 100
r e s p o n s i v e n e s s to c o u n t e r a c t u n f a v o u r a b l e genes a n d , therefore, to p r o l o n g life s p a n a n d i m p r o v e the b i o l o gical q u a l i t y o f life, h o p e f u l l y w i t h a n a c c e p t a b l e risk o f also i n c r e a s i n g a u t o r e a c t i v i t y .
References [1] [2] [3] [4]
Kubo, M. and Cinader, B. (1990) Immunol. Lett. 24, 133. Walford, R.L. (1974) Fed. Proc. 33, 2020. Makinodan, T. and Adler W.H. (1975) Fed. Proc. 34, 153. Makinodan, T., Albright, J.W., Good, P.I., Peter, C.P. and Heidrick, M.L. (1976) Immunology 31,903. [5] Miller, R.A. (1984) J. Immunol. 132, 63. [6] Miller, R.A. (1991) Int. Rev. Cytol. 124, 187. [7] Hirokawa, K. and Makinodan, T. (1975) J. Immunol. 114, 1659. [8] Farr, A.G. and Sideman, C.L. (1984) J. Immunol. 133, 98. [9] Goldstein, A.L., Low, T.L.K., Thurman, G.B., Zatz, M.M., Hall, N., Chen, J., Hu, S.K., Naylor, P.B. and McClure, J.E. (1981) in: Recent Progress in Hormone Research (R.O. Greef, Ed.) Vol. 37, pp. 369-412, Academic Press, New York. [10] Carding, S.R., Hayday, A.C. and Bottomly, K. (1991) Immunol. Today 12, 239. [11] Globerson, A., Eren, R., Abel, L. and Ben-Menahem, D. (1990) Biomedical Advances in Aging (A.L. Goldstein, Ed.), pp. 363-373, Plenum Press, New York. [12] Dobken, J., Weksler, M.E. and Siskind, G.W. (1980) Cell. Immunol. 55, 66.
[13] Charreire, J. and Bach, J.F. (1975) Proc. Natl. Acad. Sci. USA 72, 3201. [14] Naor, D., Bonavida, B. and Walford R.L. (1976) J. Immunol. 117, 2204. [15] Miller, J.F.A.P. (1992) in: Advances in Tumor Immunology and Allergic Disorders (F. Dammacco, Ed.), pp. 413-456, ediermes, Milano. [16] Daynes, R.A. and Araneo, B.A. (1992) Aging, lmmunol. Infect. Dis. 13, 135. [17] Frasca, D., Adorini, L., Mancini, C. and Doria, G. (1986) Immunopharmacology 11, 155. [18] Barcellini, W., Meroni, P.L., Frasca, D., Sguotti, C., Borghi, M.O., Uberti-Foppa, C., Buzzetti, P., Lazzarin, A., Doria, G., Moroni, M. and Zanussi, C. (1987) Clin. Exp. Immunol. 67, 537. [19] Goso, C., Frasca, D. and Doria, G. (1992) Clin. Exp. Immunol. 87, 346. [20] Caroleo, M.C., Frasca, D., Nistic6, G. and Doria, G. (1992) Immunopharmacology 23, 81. [21] Zhao, K.S., Mancini, C. and Doria, G. (1990) Immunopharmacology 20, 225. [22] Frasca, D., Adorini, L., Landolfo, S. and Doria, G. (1985) J. Immunol. 134, 3907. [23] Covelli, V., Mouton, D., Di Majo, V., Bouthillier, Y., Bangrazi, C., Mevel, J.C., Rebessi, S., Doria, G. and Biozzi, G. (1989) J. Immunol. 142, 1224. [24] Biozzi, G., Mouton, D., Sant'Anna, O.A., Passos, H.C., Gennari, M., Reis, M.H., Ferreira, V.C.H., Heumann, A.M., Bouthillier, Y., Ibanez, O.M., Stiffel, C. and Siqueira, M. (1979) Curr. Top. Microbiol. Immunol. 85, 31.
233
Ageing and genetic control of immune responsiveness Gino Doria* and Daniela Frasca Laboratory of lmmunology, AMB-EFF, ENEA Casaccia, 00060 S. Maria Galeria, Rome, Italy (Accepted 29 January 1994)
1.
Summary
Ageing is associated with a progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena [1,2]. Many studies have been focussed on the mechanisms of the immunologic features of ageing. Alterations in cellular components of the immune system rather than in the extracellular milieu seem to account for most of the variations of immune competence in ageing [3].
2. Introduction
The decrease in immune reactivity with increasing age may reflect multiple events, affecting cell proliferation and differentiation, leading to reduction in cell number and function within one or more cell populations [4]. Limiting dilution analysis of immune competent T cells indicates that the frequency of responding cells declines with ageing but the progeny of each cell maintains full proliferative capacity and immune competence [5]. These age-related changes in the T-cell population are not clearly connected with modifications of the CD4+/CD8 ÷ cell ratio but seem to reflect a shift from CD45RA + to CD45RO ÷ cell subsets, entailing a decreased sensitivity to mitogens and a reduction in both IL-2 production and IL-2R expression [6]. The decline in Tcell immune responsiveness to exogenous antigens has been attributed to thymus involution consisting
Key words: Exogenous antigen; Autoimmunity; Interleukin-2; Cell proliferation; Cell differentiation; Thymus *Corresponding author: Dr. G. Doria, Laboratory of Immunology, AMB-EFF, ENEA Casaccia, Via Anguillarese 301, 00060 S. Maria Galeria, Rome, Italy. Tel.: + 39 6 30483619; Fax: + 39 6 30483644. SSDI 0 1 6 5 - 2 4 7 8 ( 9 4 ) 0 0 0 6 1 - U
of a fall in the capacity to induce intrathymic T-cell growth and differentiation [7]. Alterations of the intrathymic environment may be bound to reduced expression of MHC molecules on epithelial cells [8] and decreased production and secretion of thymic hormones [9] and cytokines [10]. Also ageing of bone marrow stem cells may contribute to thymus involution as they display reduced potential to differentiate into T cells upon transfer from old donors to young thymic environment [11]. The increasing incidence of autoimmunity in ageing is difficult to reconcile with the progressive immunodeficiency to exogenous antigens. Beside the intrinsic B-cell resistance to tolerance induction in ageing [12], the concomitant appearance of autoreactive T cells [13,14] has suggested that the mechanisms of the development and maintenance of self-tolerance deteriorate with ageing. Age-related accumulation of thymic stromal damage may, indeed, hamper negative selection leading to ineffective elimination of autoreactive T-cell clones. Furthermore, ageing may also affect the peripheral mechanisms of tolerance induction by reducing cell sensitivity to clonal anergy, cell production of inhibitory lymphokines, or anti-idiotype cell reactivity against self-antigen receptors [15].
3. Immune responsiveness in senescence
Therapeutic intervention in ageing is a difficult task as it requires very accurate protocols to reach the antithetic objectives of correcting immune defects and mitigating autoreactivity. Restoration of immune responsiveness in old individuals was achieved by hormone administration [16-20] and by other treatments [21,22]. In one [19] of these studies, T helper cell activity was found to have increased in old mice shortly after the injection of a single dose of
TABLE 1 EFFECT OF THYMIC HORMONES ON TH CELL ACTIVITY IN OLD MICE Synthetic thymic hormones
Doubling dose ng*
Thymic humoral factor (THF-72) Thymopentin (TP5) Thymosin-ctl (Thy-al)
Relative efficiency
0.17 (2.45) 6,67 (1.87) 229.55 (1.56)
Weight
Molarity
1350 34 1
414 8 1
THF-72:8 aa, MW 954; TP5:5 aa, MW 776; Thy-ah 28 aa, MW 3110. *Error factor by which the dose should be multiplied or divided to obtain the variation due to one S.E.
synthetic thymosin-al (Thy-al), thymopentin (TP5), or thymic humoral factor (THF-72). The relative efficacy of these thymic hormones was assessed over a wide dose range and it was found that THF-72 and TP5 were 400-fold and 8-fold more effective than Thy-~l, respectively (Table 1). Immunorestoration, however, suffers the risk of increasing autoreactivity as well. Thus, careful clinical examination should aim at a risk/benefit evaluation before any immunorestorative intervention. It should be pointed out that it is unclear what should be the optimal level of immune responsiveness in senescence to maintain or prolong the life span and improve the biological quality of life. A genetic approach to this issue indicated that high immune responsiveness is positively correlated with life span and resistance to cancer and other illnesses [23]. Mice of a genetically heterogeneous population were selected (Selection II) for high (H) or low (L) agglutinin response to sheep red blood cells (SRBC) for 39 generations. Thereafter, the parental line (H and L), cross (F1), intercross (F2), and backcross (BcH and BcL) progenies were immunized with SRBC, tested for the agglutinin response, and then followed until spontaneous death to detect tumors and inflammatory diseases. Genetic analysis of the result of Selection II indicated that immune responsiveness is a
quantitative trait under polygenic control as it is regulated by 5-7 independent loci. Selection and segregation of this set of genes affect not only the agglutinin response to SRBC but also immune responses to other immunogens unrelated to the selection antigen [24]. Table 2 shows that the higher agglutinin titer is correlated with longevity and low incidence of lymphomas, solid tumors, and chronic nephritis. Pleiotropic action of the same genes or linkage of different genes that control these characters may explain why selection and segregation of immune responsiveness bring about concomitant changes in the other characters. The data, however, are also compatible with the possibility that it is the immune system, rather than the selected genes, that directly influences life span and disease incidence. The hypothesis of a determinant role of the immune system would receive further support if the life span of L mice could be extended by manipulations that enhance their immune performance. This issue is presently being investigated in our laboratory.
4. Conclusion
In conclusion, this immunologic approach to ageing may lead to the possibility of increasing immune
TABLE 2 IMMUNE RESPONSE, LIFE SPAN, AND MORBIDITY IN MICE FROM SELECTION II Mouse population
H L FI F2 BcH BcL
No. of mice
134 123 153 192 174 102
Agglutinin log2 titer (mean ± SD)
11.4 ± 0.8
5.2 9.4 9.8 10.8 7.5
*Age-adjusted percentage.
232
___ 1.0 ± 0.7 ± 1.2 ± 0.9 ± 1.4
Life span (days)
Disease incidence*
Total population (mean ± SD)
Last 20% survivors (mean ± SD)
Lymphomas
Solid tumours
Chronic nephritis
612 346 549 513 530 464
752 444 747 681 748 608
14 62 45 32 40 40
27 45 38 38 30 36
18 70 12 19 9 52
± ± ± ± ± ±
148 110 186 183 215 158
± 64 ± 74 ± 62 ± 85 ± 71 ± 100
r e s p o n s i v e n e s s to c o u n t e r a c t u n f a v o u r a b l e genes a n d , therefore, to p r o l o n g life s p a n a n d i m p r o v e the b i o l o gical q u a l i t y o f life, h o p e f u l l y w i t h a n a c c e p t a b l e risk o f also i n c r e a s i n g a u t o r e a c t i v i t y .
References [1] [2] [3] [4]
Kubo, M. and Cinader, B. (1990) Immunol. Lett. 24, 133. Walford, R.L. (1974) Fed. Proc. 33, 2020. Makinodan, T. and Adler W.H. (1975) Fed. Proc. 34, 153. Makinodan, T., Albright, J.W., Good, P.I., Peter, C.P. and Heidrick, M.L. (1976) Immunology 31,903. [5] Miller, R.A. (1984) J. Immunol. 132, 63. [6] Miller, R.A. (1991) Int. Rev. Cytol. 124, 187. [7] Hirokawa, K. and Makinodan, T. (1975) J. Immunol. 114, 1659. [8] Farr, A.G. and Sideman, C.L. (1984) J. Immunol. 133, 98. [9] Goldstein, A.L., Low, T.L.K., Thurman, G.B., Zatz, M.M., Hall, N., Chen, J., Hu, S.K., Naylor, P.B. and McClure, J.E. (1981) in: Recent Progress in Hormone Research (R.O. Greef, Ed.) Vol. 37, pp. 369-412, Academic Press, New York. [10] Carding, S.R., Hayday, A.C. and Bottomly, K. (1991) Immunol. Today 12, 239. [11] Globerson, A., Eren, R., Abel, L. and Ben-Menahem, D. (1990) Biomedical Advances in Aging (A.L. Goldstein, Ed.), pp. 363-373, Plenum Press, New York. [12] Dobken, J., Weksler, M.E. and Siskind, G.W. (1980) Cell. Immunol. 55, 66.
[13] Charreire, J. and Bach, J.F. (1975) Proc. Natl. Acad. Sci. USA 72, 3201. [14] Naor, D., Bonavida, B. and Walford R.L. (1976) J. Immunol. 117, 2204. [15] Miller, J.F.A.P. (1992) in: Advances in Tumor Immunology and Allergic Disorders (F. Dammacco, Ed.), pp. 413-456, ediermes, Milano. [16] Daynes, R.A. and Araneo, B.A. (1992) Aging, lmmunol. Infect. Dis. 13, 135. [17] Frasca, D., Adorini, L., Mancini, C. and Doria, G. (1986) Immunopharmacology 11, 155. [18] Barcellini, W., Meroni, P.L., Frasca, D., Sguotti, C., Borghi, M.O., Uberti-Foppa, C., Buzzetti, P., Lazzarin, A., Doria, G., Moroni, M. and Zanussi, C. (1987) Clin. Exp. Immunol. 67, 537. [19] Goso, C., Frasca, D. and Doria, G. (1992) Clin. Exp. Immunol. 87, 346. [20] Caroleo, M.C., Frasca, D., Nistic6, G. and Doria, G. (1992) Immunopharmacology 23, 81. [21] Zhao, K.S., Mancini, C. and Doria, G. (1990) Immunopharmacology 20, 225. [22] Frasca, D., Adorini, L., Landolfo, S. and Doria, G. (1985) J. Immunol. 134, 3907. [23] Covelli, V., Mouton, D., Di Majo, V., Bouthillier, Y., Bangrazi, C., Mevel, J.C., Rebessi, S., Doria, G. and Biozzi, G. (1989) J. Immunol. 142, 1224. [24] Biozzi, G., Mouton, D., Sant'Anna, O.A., Passos, H.C., Gennari, M., Reis, M.H., Ferreira, V.C.H., Heumann, A.M., Bouthillier, Y., Ibanez, O.M., Stiffel, C. and Siqueira, M. (1979) Curr. Top. Microbiol. Immunol. 85, 31.
233