Immunology Today, voL 6, No. 10, 1985
Influences on life-span of NZB/W mice SIR,
Recently, diet has been determined to be a factor which can influence the life span of animals which spontaneously develop systemic lupus erythematosus (SLE) (Immunol. Today 1985, 6, 120). While conducting studies on the influence of dietary zinc on survival in N Z B / W mice, we noted that N Z B / W mice housed in box cages with sawdust bedding and maintained on a normal rodent pellet diet had a shorter life span than animals (obtained as part of the same lot) housed in stainless steel wire mesh cages and fed the same diet. Therefore, we re-evaluated this observation. Twenty N Z B / W female mice were obtained from Jackson Laboratories. T e n were housed in a single box cage with sawdust bedding and two groups with five animals each were housed in stainless steel wire mesh cages. Each were fed a rodent pellet diet (Ralston Purina, St. Louis, M e ) and deionized water ad libiturn. T h e animals were not handled during the experimental period, and no serum was col-
More about NK cells and regulation of B cell activity SIR, The July 1984 issue of Immunology Today contained an interesting Rostrum article about the possible regulatory functions of natural killer (NK) cells on B cell activity I . Since new information on this topic has become available, we felt that the problem had to be revised and that a special emphasis should be placed on h u m a n cells. In man, most N K activity is exerted by a morphologically homogeneous subpopulation of lymphoid cells that have been referred to as large granular lymphocytes (LGL) 2. Two lines of evidence strongly suggest that h u m a n B cells are susceptible to L G L regulation. (1) L G L suppress in-vitro immuneglobulin (Ig) production by (i) in vivo generated, antigen specific lymphoblastoid B cells 3 and (ii) pokeweed mitogen ( P W M ) activated mononuclear cells4'S; in all these studies suppressor L G L expressed the Leu 7 marker detected by the corresponding monoclonal antibody. In the system that made use of lymphoblastoid B cells the inhibitory activity was abrogated by the
287 lected for serologic studies. T h e animals were housed in the same room with the box and mesh cages being approximately four feet from each other. The purpose of the experiment was to determine if housing conditions influenced life span. T h e accompanying figure indicates the survival rate of the animals in the two different living environments. The same data were obtained during our initial observation. Thus, we have reproduced an increased life span i n N Z B / W mice which is related to the housing environment. O n e can only speculate as to the reason for this difference. Pathogens pre-
sent in the sawdust or in the animals' excretions may be factors. Thus, in addition to immunologic factors, diet and living environment can influence survival in N Z B / W mice. Whether these latter factors work by altering the i m m u n e system in the animals is a logical area of further exploration. ~[]
BRUCE S. RABIN
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
NZB/W survival in box cages vs wire mesh cages 100' 9O
k~..~.
-~
Wire mesh cages
80 _ 70 "60 "~ 50 co 40 o~ 30
20 10 30
"~JK
32
34
36
30
40
42
44
46
48
50
52
54
Age (weeks)
addition of low numbers of K 562 ceils and some correlation was found between inhibition of Ig production and the N K capacity of the inhibitory cells 3, suggesting that cytotoxicity was possibly responsible for the observed suppressive effect. T h e target cells for L G L inhibition of Ig production may be the lymphoblastoid B cells themselves 3 or, alternatively, the helper T cells 4. (2) Beside suppression, L G L may promote B-cell proliferation. For example, a subset of h u m a n L G L with a Leu 7 + O K M 1 +, E rosette-, H L A - D R - , Leu 11- surface phenotype releases B cell growth factor (BCGF) in vitro, upon activation with P H A 6. This particular L G L s u b s e t has a poor N K activity, as expected from its Leu 11- surface phenotype, and does not produce IL-1 or IL-26. O t h e r relevant regulatory activities of L G L emerged from a n u m b e r of recent studies: L G L release factors active on T cell proliferation 7-9 and synthesize burst promoting activity t° and colony stimulating factor a. In addition, L G L may inhibit the growth of pluripotent hemopoietic stem ceils" and of granulocyte-macrophage committed progenitor cells 11,~2by direct
contact, possibly involving the cell-cell release of cytotoxic factors tl. Until recently L G L have been equated to N K cells. Now the available evidence suggests that not all L G L have cytotoxic activity and that L G L subsets exert regulatory functions of various types a-5'7-1x. Heterogeneity of L G L is also suggested by surface marker analysis with monoclonal antibodies. At present it is not known whether or not L G L derive from the same lineage or else are a heterogeneous cell population originating from disparate lineages (T cells, non-T/non-B cells, or even myeloid cells). Certainly, it would be appealing to speculate that L G L all belong to the same lineage and that they have been selected in evolution to regulate proliferation of other cell types.
[] V. PISTOIA F. COZZOLINO M. FERRARINI Seroizio di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancroand Istituto di Oncologia, Universith di Geneva, Viale Benedetto XV, 10 16132 - Geneva, Italy.
288
References 1 James, K. and Ritchie, W. S. (1984) Irnmunol. Today 5, 193-194 2 Timonen, T , Ortaldo, J. R. and Herberman, R. B. (1981)J. Exp. Med. 153, 569- 582 3 Brieva,J. A., Targan, S. and Stevens, R. H. (1984).]. Immunol. 132, 611-615 4 Arai, S., Yarnamoto, H., Ito, K. and Kumagai, K. (1983)J. Immunol. 131,651657 5 Tilden, A., Abo, T. and Balch, C. M. (1983)
Therapy for AIDS SIR, It is now widely accepted that the acquired immunodeficiency syndrome (AIDS) is caused by the h u m a n T-lymphotropic virus type III ( H T L V - I I I ) , which infects and destroys T4 + h e l p e r - i n d u c e r lymphocytes. Proliferation a n d consequent cytopathicity of the virus appears to occur only in T4 + cells which have u n d e r g o n e activationS; indeed, the existence of raised levels of activated T 4 + cells in the circulation and l y m p h o i d tissues o f high risk groups m a y well be a major predisposing factor for the development of the full-blown syndrome. Activated T 4 + cells will proliferate in response to interleukin 2 (IL-2), and this agent appears to partially reconstitute i m m u n e responsiveness in vitro in the cells of some A I D S patients 2 *. Consequently, several groups have used IL-2 as a potential i m m u n o restorative in vivo, even t h o u g h there would appear to be serious objections to this approach. IL-2 will e x p a n d both the activated T 4 + population, providing fertile g r o u n d for virus proliferation, and the activated T8 + subset, included a m o n g s t which are suppressors of
Immunology Today, vol. 6, No. 10, 1985 J. ImmunoL 130, 1171-1175 6 Pistoia, V., Cozzolino, F., Torcia, M., Castigli, E. and Ferrarini, M. (1985) J. Immunol. 134, 3179-3184 7 Pistoia, V., Nocera, A., Ghio, R., Leprini, A., Perata, A., Pistone, M. A. and Ferrarini, M. (1982) Exp. Hematol. 11, 249-259 8 Kasahara, T., Djeu, J. Y., Dougherty, J. F. and Oppertheim, J. J. (1983)J. Immunol. 131, 2379-2383 9 Scala, 'G., Anavena, P., Djeu, J. Y., i m m u n e effector systems. In vivo use of IL-2 may, therefore, increase rather than decrease the t e m p o of disease progression. It is most unlikely that i m m u n o reconstitution could succeed while virus remains to infect any newly induced i m m u n o c o m p e t e n t T4 + cells. C e r t a i n anti-viral agents, notably ribavirin 5 and s u r a m i n 6, have shown promise as inhibitors o f virus infectivity a n d replication in vitro, a n d are now being evaluated in pilot trials. If it should become possible to eliminate H T L V - I I I in vivo, bone m a r r o w transplantation could succeed 7, but suitable donors will not be available in most cases. H o w e v e r , autologous bone m a r r o w could be obtained at an early stage in the disease, be p u r g e d of virus-infected cells by treatm e n t in vitro with anti-viral agents, or possibly with O K T 4 monoclonal antibody to remove chronically infected cells, and be stored frozen for reinfusion at a suitable time. H e a l t h y individuals exposed to H T L V - I I I , who presumably have normal, low levels of activated T4 + cells, m a y h a r b o u r and transmit the virus while r e m a i n i n g symptom-free. It is possible that disease could develop in carriers if infected T 4 + cells become
Kasahara, T., Ortaldo, J. R., Herberrnan, R. B. and Oppenheim, J. J. (1984) Nature (London) 309, 56-59 10 Pistoia, V., Ghio, R., Nocera, A., Leprini, A., Perata, A. and Ferrarini, M. (1985)Blood 65, 464-472 11 Degli Antoni, G., Perussia, B., Mangoni, L. and Trinchieri, G. (1985)J. Exp. Med. 161, 1152-1168 12 Hanson, M., Beran, M., Anderson, B. and Kiessling, R. (1982) jr. Immunol. 129, 126-132 activated and thus supportive of virus replication. This implies that every effort should be m a d e to eliminate latent virus in healthy individuals found to have H T L V - I I I antibodies.
References 1 Montagnier, L., Chermann, J. C., Barr~Sinoussi, F. et al. (1984) in Human T-ceU lo~kaemia/lymphoma viruses (Gallo, R. C., Essex, M. and Gross, L. eds), pp. 363-379, Cold Spring Harbor Laboratories, New York 2 Gupta, S., GiUis, S., Thornton, M. and Goldberg, M. (1984) Clin. Exp. Immunol. 58, 395-401 3 Lifson, J. D., Benike, C.J., Mark, D. F., et al. (1984) Lancet i 698-702 4 Sheridan, J. F., Aurelian, L., Donnenberg, A. D. and Quinn, T. C. (1984)J. Clin. Immunol. 4, 304-311 5 McCormick, J. B., Getehen, J. P., Mitchell, S. W. and Hicks, D, R. (1984) Lancet ii, 1366-1369 6 Mitsuya, H., Popovic, M., Yarchoan, R., et al. (1984) Science 226, 172-174 7 Lane, H. C., Masur, H., Longo, D. L., etal. (1984) N. Engl. J. Med. 311, 1099-1103 BRIAN M. JONES University of Hong Kong, Department of Pathology, Queen Ma?7 Hospital Compound, Hong Kong.
Modulation of immunity by drugs SIR, In their article (Immunol. Today, 1985, 6, 115-117), J . E. Blalock and E. M . Smith misinterpret and/or misquote work done by G. Maestroni and myself and published in several journals. W e have never used a ' n e u r o p e p t i d e h o r m o n e cocktail' for successful allograft transplantation. I n our work on the pharmacological control of the i m m u n e response, we published in 1977 •a n d 1978 a series of papers ~-3 in which we d e m o n s t r a t e d that a combination of drugs, namely the alpha-blocker phentolamine, the d o p a m i n e r g i c receptor blocker haloperidol a n d the precursor of serotonin, 5-hydroxytryptophan, completely abrogated the p r i m a r y and
m e m o r y response to antigens. A com~ bination of polypeptide h o r m o n e s (adrenocorticotrophic h o r m o n e , luteotropic and follicle stimulating h o r m o n e ) could p r e v e n t the action of the three drugs. W e proposed at that time that lymphocytes act as messengers to the neuroendocrine system and that intervention with drugs acting on neuroendocrine regulation might permit the control of the i m m u n e response. H o w e v e r , since the authors o f the article m e n t i o n allograft transplantation, m a y b e they refer to another kind of approach in which bone m a r r o w - d e r i v e d factors p e r m i t the safe transplantation Of allogeneic bone m a r r o w between histoincompatible
mouse strains 4. T h e chemical nature o f the m a r r o w factors is still u n k n o w n and cannot certainly be classified as ' n e u r o peptide h o r m o n e cocktail'. [z]-]
References 1 Pierpaoli, W. and Maestroni, G. J. M. (1977) Cell Imraunol. 31,355-363 2 Pierpaoli, W. and Maestroni, G. J. M. (1978) Immunology 34, 419-430 3 Pierpaoli, W. and Maestroni, G. J. M. (1978).], Immunol. 120, 1600-1603 4 Pierpaoli, W., Maestroni, G. J. M. and Saehe, E. (1981) Cell Immunol. 57, 219-228 WALTER PIERPAOLI Institute for Integrative Biomedical Research, CH-8123 Ebmatingen, Lohwisstrasse 50, Switzerland.
Influences on life-span of NZB/W mice SIR,
Recently, diet has been determined to be a factor which can influence the life span of animals which spontaneously develop systemic lupus erythematosus (SLE) (Immunol. Today 1985, 6, 120). While conducting studies on the influence of dietary zinc on survival in N Z B / W mice, we noted that N Z B / W mice housed in box cages with sawdust bedding and maintained on a normal rodent pellet diet had a shorter life span than animals (obtained as part of the same lot) housed in stainless steel wire mesh cages and fed the same diet. Therefore, we re-evaluated this observation. Twenty N Z B / W female mice were obtained from Jackson Laboratories. T e n were housed in a single box cage with sawdust bedding and two groups with five animals each were housed in stainless steel wire mesh cages. Each were fed a rodent pellet diet (Ralston Purina, St. Louis, M e ) and deionized water ad libiturn. T h e animals were not handled during the experimental period, and no serum was col-
More about NK cells and regulation of B cell activity SIR, The July 1984 issue of Immunology Today contained an interesting Rostrum article about the possible regulatory functions of natural killer (NK) cells on B cell activity I . Since new information on this topic has become available, we felt that the problem had to be revised and that a special emphasis should be placed on h u m a n cells. In man, most N K activity is exerted by a morphologically homogeneous subpopulation of lymphoid cells that have been referred to as large granular lymphocytes (LGL) 2. Two lines of evidence strongly suggest that h u m a n B cells are susceptible to L G L regulation. (1) L G L suppress in-vitro immuneglobulin (Ig) production by (i) in vivo generated, antigen specific lymphoblastoid B cells 3 and (ii) pokeweed mitogen ( P W M ) activated mononuclear cells4'S; in all these studies suppressor L G L expressed the Leu 7 marker detected by the corresponding monoclonal antibody. In the system that made use of lymphoblastoid B cells the inhibitory activity was abrogated by the
287 lected for serologic studies. T h e animals were housed in the same room with the box and mesh cages being approximately four feet from each other. The purpose of the experiment was to determine if housing conditions influenced life span. T h e accompanying figure indicates the survival rate of the animals in the two different living environments. The same data were obtained during our initial observation. Thus, we have reproduced an increased life span i n N Z B / W mice which is related to the housing environment. O n e can only speculate as to the reason for this difference. Pathogens pre-
sent in the sawdust or in the animals' excretions may be factors. Thus, in addition to immunologic factors, diet and living environment can influence survival in N Z B / W mice. Whether these latter factors work by altering the i m m u n e system in the animals is a logical area of further exploration. ~[]
BRUCE S. RABIN
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
NZB/W survival in box cages vs wire mesh cages 100' 9O
k~..~.
-~
Wire mesh cages
80 _ 70 "60 "~ 50 co 40 o~ 30
20 10 30
"~JK
32
34
36
30
40
42
44
46
48
50
52
54
Age (weeks)
addition of low numbers of K 562 ceils and some correlation was found between inhibition of Ig production and the N K capacity of the inhibitory cells 3, suggesting that cytotoxicity was possibly responsible for the observed suppressive effect. T h e target cells for L G L inhibition of Ig production may be the lymphoblastoid B cells themselves 3 or, alternatively, the helper T cells 4. (2) Beside suppression, L G L may promote B-cell proliferation. For example, a subset of h u m a n L G L with a Leu 7 + O K M 1 +, E rosette-, H L A - D R - , Leu 11- surface phenotype releases B cell growth factor (BCGF) in vitro, upon activation with P H A 6. This particular L G L s u b s e t has a poor N K activity, as expected from its Leu 11- surface phenotype, and does not produce IL-1 or IL-26. O t h e r relevant regulatory activities of L G L emerged from a n u m b e r of recent studies: L G L release factors active on T cell proliferation 7-9 and synthesize burst promoting activity t° and colony stimulating factor a. In addition, L G L may inhibit the growth of pluripotent hemopoietic stem ceils" and of granulocyte-macrophage committed progenitor cells 11,~2by direct
contact, possibly involving the cell-cell release of cytotoxic factors tl. Until recently L G L have been equated to N K cells. Now the available evidence suggests that not all L G L have cytotoxic activity and that L G L subsets exert regulatory functions of various types a-5'7-1x. Heterogeneity of L G L is also suggested by surface marker analysis with monoclonal antibodies. At present it is not known whether or not L G L derive from the same lineage or else are a heterogeneous cell population originating from disparate lineages (T cells, non-T/non-B cells, or even myeloid cells). Certainly, it would be appealing to speculate that L G L all belong to the same lineage and that they have been selected in evolution to regulate proliferation of other cell types.
[] V. PISTOIA F. COZZOLINO M. FERRARINI Seroizio di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancroand Istituto di Oncologia, Universith di Geneva, Viale Benedetto XV, 10 16132 - Geneva, Italy.
288
References 1 James, K. and Ritchie, W. S. (1984) Irnmunol. Today 5, 193-194 2 Timonen, T , Ortaldo, J. R. and Herberman, R. B. (1981)J. Exp. Med. 153, 569- 582 3 Brieva,J. A., Targan, S. and Stevens, R. H. (1984).]. Immunol. 132, 611-615 4 Arai, S., Yarnamoto, H., Ito, K. and Kumagai, K. (1983)J. Immunol. 131,651657 5 Tilden, A., Abo, T. and Balch, C. M. (1983)
Therapy for AIDS SIR, It is now widely accepted that the acquired immunodeficiency syndrome (AIDS) is caused by the h u m a n T-lymphotropic virus type III ( H T L V - I I I ) , which infects and destroys T4 + h e l p e r - i n d u c e r lymphocytes. Proliferation a n d consequent cytopathicity of the virus appears to occur only in T4 + cells which have u n d e r g o n e activationS; indeed, the existence of raised levels of activated T 4 + cells in the circulation and l y m p h o i d tissues o f high risk groups m a y well be a major predisposing factor for the development of the full-blown syndrome. Activated T 4 + cells will proliferate in response to interleukin 2 (IL-2), and this agent appears to partially reconstitute i m m u n e responsiveness in vitro in the cells of some A I D S patients 2 *. Consequently, several groups have used IL-2 as a potential i m m u n o restorative in vivo, even t h o u g h there would appear to be serious objections to this approach. IL-2 will e x p a n d both the activated T 4 + population, providing fertile g r o u n d for virus proliferation, and the activated T8 + subset, included a m o n g s t which are suppressors of
Immunology Today, vol. 6, No. 10, 1985 J. ImmunoL 130, 1171-1175 6 Pistoia, V., Cozzolino, F., Torcia, M., Castigli, E. and Ferrarini, M. (1985) J. Immunol. 134, 3179-3184 7 Pistoia, V., Nocera, A., Ghio, R., Leprini, A., Perata, A., Pistone, M. A. and Ferrarini, M. (1982) Exp. Hematol. 11, 249-259 8 Kasahara, T., Djeu, J. Y., Dougherty, J. F. and Oppertheim, J. J. (1983)J. Immunol. 131, 2379-2383 9 Scala, 'G., Anavena, P., Djeu, J. Y., i m m u n e effector systems. In vivo use of IL-2 may, therefore, increase rather than decrease the t e m p o of disease progression. It is most unlikely that i m m u n o reconstitution could succeed while virus remains to infect any newly induced i m m u n o c o m p e t e n t T4 + cells. C e r t a i n anti-viral agents, notably ribavirin 5 and s u r a m i n 6, have shown promise as inhibitors o f virus infectivity a n d replication in vitro, a n d are now being evaluated in pilot trials. If it should become possible to eliminate H T L V - I I I in vivo, bone m a r r o w transplantation could succeed 7, but suitable donors will not be available in most cases. H o w e v e r , autologous bone m a r r o w could be obtained at an early stage in the disease, be p u r g e d of virus-infected cells by treatm e n t in vitro with anti-viral agents, or possibly with O K T 4 monoclonal antibody to remove chronically infected cells, and be stored frozen for reinfusion at a suitable time. H e a l t h y individuals exposed to H T L V - I I I , who presumably have normal, low levels of activated T4 + cells, m a y h a r b o u r and transmit the virus while r e m a i n i n g symptom-free. It is possible that disease could develop in carriers if infected T 4 + cells become
Kasahara, T., Ortaldo, J. R., Herberrnan, R. B. and Oppenheim, J. J. (1984) Nature (London) 309, 56-59 10 Pistoia, V., Ghio, R., Nocera, A., Leprini, A., Perata, A. and Ferrarini, M. (1985)Blood 65, 464-472 11 Degli Antoni, G., Perussia, B., Mangoni, L. and Trinchieri, G. (1985)J. Exp. Med. 161, 1152-1168 12 Hanson, M., Beran, M., Anderson, B. and Kiessling, R. (1982) jr. Immunol. 129, 126-132 activated and thus supportive of virus replication. This implies that every effort should be m a d e to eliminate latent virus in healthy individuals found to have H T L V - I I I antibodies.
References 1 Montagnier, L., Chermann, J. C., Barr~Sinoussi, F. et al. (1984) in Human T-ceU lo~kaemia/lymphoma viruses (Gallo, R. C., Essex, M. and Gross, L. eds), pp. 363-379, Cold Spring Harbor Laboratories, New York 2 Gupta, S., GiUis, S., Thornton, M. and Goldberg, M. (1984) Clin. Exp. Immunol. 58, 395-401 3 Lifson, J. D., Benike, C.J., Mark, D. F., et al. (1984) Lancet i 698-702 4 Sheridan, J. F., Aurelian, L., Donnenberg, A. D. and Quinn, T. C. (1984)J. Clin. Immunol. 4, 304-311 5 McCormick, J. B., Getehen, J. P., Mitchell, S. W. and Hicks, D, R. (1984) Lancet ii, 1366-1369 6 Mitsuya, H., Popovic, M., Yarchoan, R., et al. (1984) Science 226, 172-174 7 Lane, H. C., Masur, H., Longo, D. L., etal. (1984) N. Engl. J. Med. 311, 1099-1103 BRIAN M. JONES University of Hong Kong, Department of Pathology, Queen Ma?7 Hospital Compound, Hong Kong.
Modulation of immunity by drugs SIR, In their article (Immunol. Today, 1985, 6, 115-117), J . E. Blalock and E. M . Smith misinterpret and/or misquote work done by G. Maestroni and myself and published in several journals. W e have never used a ' n e u r o p e p t i d e h o r m o n e cocktail' for successful allograft transplantation. I n our work on the pharmacological control of the i m m u n e response, we published in 1977 •a n d 1978 a series of papers ~-3 in which we d e m o n s t r a t e d that a combination of drugs, namely the alpha-blocker phentolamine, the d o p a m i n e r g i c receptor blocker haloperidol a n d the precursor of serotonin, 5-hydroxytryptophan, completely abrogated the p r i m a r y and
m e m o r y response to antigens. A com~ bination of polypeptide h o r m o n e s (adrenocorticotrophic h o r m o n e , luteotropic and follicle stimulating h o r m o n e ) could p r e v e n t the action of the three drugs. W e proposed at that time that lymphocytes act as messengers to the neuroendocrine system and that intervention with drugs acting on neuroendocrine regulation might permit the control of the i m m u n e response. H o w e v e r , since the authors o f the article m e n t i o n allograft transplantation, m a y b e they refer to another kind of approach in which bone m a r r o w - d e r i v e d factors p e r m i t the safe transplantation Of allogeneic bone m a r r o w between histoincompatible
mouse strains 4. T h e chemical nature o f the m a r r o w factors is still u n k n o w n and cannot certainly be classified as ' n e u r o peptide h o r m o n e cocktail'. [z]-]
References 1 Pierpaoli, W. and Maestroni, G. J. M. (1977) Cell Imraunol. 31,355-363 2 Pierpaoli, W. and Maestroni, G. J. M. (1978) Immunology 34, 419-430 3 Pierpaoli, W. and Maestroni, G. J. M. (1978).], Immunol. 120, 1600-1603 4 Pierpaoli, W., Maestroni, G. J. M. and Saehe, E. (1981) Cell Immunol. 57, 219-228 WALTER PIERPAOLI Institute for Integrative Biomedical Research, CH-8123 Ebmatingen, Lohwisstrasse 50, Switzerland.
