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Lithium as an immunologic adjuvant
Medical
@
6: t-6, 1980 Livingstone
Hypotheses
Churchill
LITHIUM AS AN IMMUNOLOGICADJUVANT. Louis Shenkmsn,William Borkomky and Bazon Shopsin. Departmentof Medicine, Pediatricsand Psychiatry,New York UniversityMedicsl Center, 550 First Avenue, New York, New York 10016. AESTRACT Lithium, an adenylatecyclase inhibitor,stimulatesa variety of in vitro indices of immune function,includingproliferationof lymphocytesin response to mitogens,rosette formationby T-cells and phagocytosisby macrophages. Lithium enhancesthese immunologicresponsesat concentrations comparableto those achievedin patientsreceivinglithium for treatment of manic-depressivedisorders. Lithium may prove to have importanttherapeuticapplicationsas an immune adjuvant,particularlyin immune deficiencystates associatedwith excessiveC-AMP production. INTRODUCTION Lithium has become an importanttherapeuticmodality in the treatmentof affectivedisorders. In this Hypothesis,we propose that lithiummay prove to be an importantnew form of therapy for certain immune deficiency states. Althoughits exact mode of action on the centralnervous system is not known, lithium has been shown to interferewith a variety of adenylate cyclasesystems (1). The occasionaldeveloInnent of goiter or hypothrroidism in patientsreceivinglithiumhas been related to an inhibition of TSH-mediatedadenylatecyclaseactivationin the thyroid cell (2), or to interferencewith post-cyclicAMP events (3). Similarly,the polyuria and decreasedability to concentrateurine associatedwith lithium therapy has been attributed,at least in part, to en inhibitionof AI&mediated cyclic AMP accumulationin renal tubular cells (4). In additionto inhibitingTSH and ADH-mediatedevents,lithium also has been found to inhibit adenylatecyclaseactivationby epinephrine,fluorideand ACTH in fat cells (5-6) , and prostaglandinEl-mediatedactivationof sdenylate cyclase in platelets(7).
The activitiesof lymphocytes,macrophagesand polymorphonuclear cells can be regulatedby alterationsin cyclic nucleotidelevels. Agents which increase cellularC-AMP usually decreaseinflammatorycell numbers, cell function,and cell product synthesisand release (8-9). An increasein lymphocyteC-AMP is associatedwith decreasedproliferationto mitogenic stimulation(lo), decreasedE-rosetteformationand stability(ll), increased suppressorcell activity (12), decreasedantibodyrelease (13), and diminishedlymphokineproduction(14). An increasein C-AMP affects monocyte-macrophage by diminishedmaturationof precursorcells (is), reduced release of acid hydrolasesand decreasedtumoricidalactivity (16). Elevationsof C-AMP affect polymorphonuclear leukocytesby decreasedmaturation of bone marrow precursors(15), reduced locomotion(lb), decreased responseto chemotactic-stimuli, d&&&hed release of acid-hydrolases (18), and suppressedsuperoxideproductionand chemoluminescent activity (19)
l
In view of these diverse inhibitoryeffects of C-AMP on immune function, it occurredto us that the lithium ion, by decreasingadenylatecyclase activityand thereby lowering intracellularC-AMP levels, may stimulate lymphocytes,macrophagesand polymorphonucleer leukocytes,and thereby act as an immune adjuvant. To test tNs hypothesis,we began by examining the -in vitro effects of lithium on several indices of cellularimmunity. EFFECTS OF LITHIUM ON LYMPHOCYTES
Figure 1: Effect of lithium on mitogenicresponseto
0-I 0
12
3
4
5
LITHIUMCONCENTRATION(mEp/Ll
As shown in Figure 1, the mitogenicresponse of human mononuclearcell preparationsto PHA was enhancedprogressivelyby lithium concentrations of 0.15 to 5 mEq/L(20). In mononuclearcell preparationsnot stimulated by PHA, lithium was not itself mitogenic. ProstaglendinEl, a potent stimulatorof adenylatecyclase,significantlyinhibitedthe responseto PHA. 2
The additionof lithium at a concentrationof as little as I.25 mEq/L reversed the inhibitoryeffect of theophyllineon PHA-indexedtx%.nsformation* These observationssupport the view that lithiummay be acting on mononuclear cells by inhibitingadenylatecyclaseactivity,and thereby enhancing their function. C-AMP is known to regulaterosette formationby T cells, and if lithium is indeed acting to decreasecyclic AMP levels, one would anticipatethat lithium should increasethe ability of lymphocytesto form rosetteswith sheep erythrocytes. Our studieshave shown that this is indeed so. Ikeincubationof lymphocytesfor two hours with lithium, 1 a, increased the number of rosette-formingcells signifi.cantly (20). Our observations on the effects of lithium on mitogenicresponseof lymphocytesand on rosette formationhave been recently confirmedby Others (21). Our current studiesfurther indicatesthat lithiummay be acting,at least in part, by inhibitingthe activityof suppressorcells (22). Other investigatorshave demonstratedenhanced-in vitro antibodyproductionby lymphocytesfrom selectedpatientswith agammaglobulinemia thought to be mediated by excessivesuppressorcell activity (12). In additionto these stimulatory_in vitro effects of lithium,we have found in preliminarystudies that mice receivinga lithium-supplemented diet, who axe challengedwith sheep erythrocytes,demonstrateenhanceddelayed hypersensitivity as measured by foot pad swelling. EFFECTSON MACROPHAGES We have also demonstratedthat lithium enhancesmacrophagesphagocytosis (20). Monocyteswere isolatedfrom peripheralblood incubatedfor 3 days in media containingvarious concentrationsof lithium. They were subsequently assayed for their ability to ingest technetium-labelled latex particles. With increasingconcentrationsof lithium,phagocytosisprogressivelyrose (Figure2). Of note is the significantenhancementof phagocyt.osis at low concentrationsof lithium,well within the therapeutic plasma levels achievedin patientsreceivinglithium for treatment of affectivedisorders. d
180-
Figure 2: Effect of lithium on phagocytosis by macrophages, as assessedby the ingestionof 99Tc-labeledlatex particles. 2 LITHIUM
4
6
CONCENTRATION
8
IO l mEq / L)
EF'F'ECTS ONPOLYMORPHONUCLMAHLEUKOCYTES Lithium administrationis known to cause neutrophilia,and this property has led to the use of lithium in patientswith chemotherapy-induced neutropenia (23). Lithium is thought to increasethe neutrophilcount by enhancingthe productionof colony-stimulating activity. In preliminary in vitro studies,Perez et al have found that lithium does not enhance -random migration,chemotaxisor enzyme release of normal IWN's. One patient, however, was found to have deficientPMN functionwhich was improved by lithium (25). This patient was a 29 year old woman with a long history of eczema and recurrentstaphylococcalend streptococcal skin infections. The only discernibleabnormalitywas completeunresponsivenessof her polymorphonuclearleukocytesto standardchemotactic stimuli. The -in vitro additionof lithium to PMN preparationsrestored the previouslydeficientchemotacticresponse,and this promptedus to treat the patient with lithium. After receivinglithium carbonate,1 gm/day for 5 weeks, the chemotacticresponsivenessof her PMN*s was found to be normal, and coincidentallyshe became free of infection. Subsequent withdrawalof lithium therapy resultedin a clinicalrelapse and return to the chemotacticabmonnality. The patient has been restartedon lithium therapy,and remains well. CONCLUSION Our observationsthat lithium enhancesa variety of -in vitro indices of immune responsesraises the possibilitythat lithiummay have therapeutic potentialin selectedpatients with immune deficiencies. Lithium may find particularapplicationin patients with abnormalitiesof lymphocyte, macrophageor polymorphonuclearleukocytefunctionrelated to elevated levels of C-AMP. An example of such an immune deficiencystate may be the depressedcellularimmunity of Hodgkin'sdfsease. A prostaglandin E2-producingsuppressorcell has been identifiedin some patients with The hyporesponsiveness to PHA in these patients Hodgkin'sdisease (26). can be reversedby indomethacin,a prostaglandin-synthetase inhibitor. Pros&la&in E may act to inhibitPHA responsivenessby activating adenylatecyclase and elevatingC-AMP levels. Our -in vitro studies have shown that lithium can reverse the inhibitoryeffects of PCE (20). To explorethe possible therapeuticimplicationsof these observations, we have begun to study the effects of lithium on the mitogenicresponses of patients with Hodgkin'sdisease. Our early studiesreveal that lithium, like indomethacin,improvesthe -in vitro responsesof some patisnts. Prostsglandinsof the E series have also been shown to inhibit the activity of interferon-activated macrophsgesof mice and to reduce their tumoricidalfunction in a MBL-2 lymphoblasticleukemiacell system (16). It would be of great interestto determinewhether lithium can reverse the inhibitoryeffects of PCE in such a system. If so, such an observation may suggest a possibletherapeuticapplicationfor lithium as an adjuvant of tumor immunity. Our findingsto date thereforesuggest that lithiummay prove to have potentialtherapeuticusefulnessin selectedpatientswith abnormalities 4
of lymphocyte,macrophageor polymorphonuclear functionrelated to elevated levels of C-AMP. If such an abnormalitycan be shown to be corrected2 vitro by lithium,then a cautioustrial of therapymay be warrantedin selectedpatients.
1. Singer I, RotenbergD. Mechanismsof Lithium Action. N Engl J Med 289: 254, 1973. 2. Wolff J, Berens SC, Jones AB. Inhibitionof Thyrotropin-stimulated Adenyl CyclaseActivityof Beef ThyroidMembranesby Low Concentrationsof Lithium ion. BiochemBiophysRes Commun 39: 77, 1970. 3. Berens SC, BernsteinRS, Robbins J et al. AntithyroidEffects of Lithium. J Clin Invest 49: 1357, 1970. Cyclic 4. Beck N, Beck BB. Effects of Lithium on Vasopressin-dependent Ampin Rat Renal Medulla. Encocrinol97: 202, 1975. 5. BenjaminWB, Fish ST, Singer I. Insulin-inducedC-AMP-independent Phosphorylationof a Fat Cell Protein:Effects of Starvingand Refeeding. BiochemSOC Tram 2r 920, 1974. 6. BirnbaumerL, Pohl SL, RodbellM. Adenyl Cyclase in Fat Cells. J Biol Chem 244s 3468, 1969. 7. Murphy DL, DonnellyBS, MoskonitzJ. Inhibitionby Lithium of ProstaglandinE1 and NorepinephrineEffects on Cyclic Adenosine MonophosphateProductionin Human Platelets. Clin Pharmacol Ther 14: 810, 1973. 8. Bourne HR, LichtensteinL&l,Melmon EL et al. Modulationof Inflammation and Immunityby Cyclic AMP. Science 184: 19, 1974. 9. GoldbergND. Cyclic Nucleotidesand Cell Function:in "CellMembranes, Biochemistry,Cell Biology and Pathology",p. 185. (WeissmanG, ClairborneR, eds). H P PublishingCo, 1975. 10. HirschhornR, GrossmanJ, WeissmanG. Effect of Cyclic 3', 5'-adenosine Monophosphateand Theophyllineon LymphocyteTransformation. Proc SOC Exp Biol Med 133: 1361, 1970. Il. ChisariFV, EdgingtonIS. Human T Lymphocyte“E" Rosette Function. I A ProcessModulatedby IntracellularCyclic AMP. J Exp Med 140: 1122, 1974. 12. Dosch H, GelfandEW. FunctionalMfferentiation of B Lymphocytesin Agammaglobulinemia.III Characterization of SpontaneousCell Activity. J 1mm~n0l 12ir 2097, 1978.
5
13. Eburne HR, Melman KL, WeinsteinY et al. In "CyclicAMP, Cell Growth and The Immune Response." (Braun W, LichtensteinIM, Parker CW, eds). New York, Springer-Verlag,1974. 14. LomnitserR, Rabson AR, KoornhogHJ. The Effects of Cyclic AMP on LeucocyteInhibitoryFactor (LIF) Productionand on the Inhibition of LeucocyteMigration. Clin Exp Immunol 24: 42, 1976. 15. Kurland J, Moore AS. The RegulatoryRole of the Macrophagein Normal and NeoplasticHemopoiesis. ExperimentalHematologyToday, p. 51. (Baum S, Ledney GD, eds). New York, Springer-Verlag,1977. 16. SchultzeRM, PavlidisNA, Stylos WA et al. Regulationof Macrophage TumoricidalFunction:A Role for Prostaglandinsof the E Series. Science 202: 320, 1978. 17. Tse RL, Phelps P, Urban D. Polymorphonuclear LeukocyteMobility in vitro VI. Effect of Purine and PyrimidineAnalogues:Possible Role of Cyclic AMP. 18. WeissmanG, Dukor P, Zurier RB. Effect of Cyclic AMP on the Release of LysosomalEnmymes from Phagocytes. Nature (London)New Biol 231: 131, 1971. Drugs and 19. LehmeyerJE, JohnstonJr AB. Effect of Anti-Inflammatory Agents that Elevate IntracellularCyclic AMP on the Release of Toxfc Oxygen Metabolitesby Phagocytes:Studies in a Model of Tissue-BoundIgG. Clin Immunol Immunopath9: 482, 1978. 20. ShenkmanL, Borkowsb W, Holmman RS et al. Enchancementof Lymphocyte and MacrophageFunction in vitro by Lithium Chloride. Clin Immunol Immunopathol10: 187, 1978. 21. Gelfend EW, Dosch H, HastingsD et al. Lithium:A Modulatorof Cyclic AMP-Dependenthrents in Lymphocytes? Science 203: 365, 1979. 22. Wadler S, Shenkman L, BorkowsIqW. Effects of Lithium on SuppressorEnriched and Suppressor-Depleted MononuclearCell Preparations. Clin Res 27: 339, 1979. 23. Stein RS, Beeman C, Ali MY et al. Lithium CarbonateAttenuationof Chemotherapy-Induced Neutropenia. New Engl J Med 297: 430, 1977. 24. Harker WG, RothsteinG, ClarksonD et al. Enhancementof ColonyStimulatingActivityProductionby Lithium. Blood 49: 263, 1977. 25. Peres HD, Kaplan H, ShenIenan L et al. Reversal of an Abmonnalityof Polymorphonuclear LeukocyteChemotaxiswith Lithium. Clinical Res 27: 353, 1979. 26. Good- JS, Messner RP, BankhurstAD et al. Prostaglandin-Producing SuppressorCells in Hodgkin'sDisease. New Engl J Med 297: 963, 1977. 6
@
6: t-6, 1980 Livingstone
Hypotheses
Churchill
LITHIUM AS AN IMMUNOLOGICADJUVANT. Louis Shenkmsn,William Borkomky and Bazon Shopsin. Departmentof Medicine, Pediatricsand Psychiatry,New York UniversityMedicsl Center, 550 First Avenue, New York, New York 10016. AESTRACT Lithium, an adenylatecyclase inhibitor,stimulatesa variety of in vitro indices of immune function,includingproliferationof lymphocytesin response to mitogens,rosette formationby T-cells and phagocytosisby macrophages. Lithium enhancesthese immunologicresponsesat concentrations comparableto those achievedin patientsreceivinglithium for treatment of manic-depressivedisorders. Lithium may prove to have importanttherapeuticapplicationsas an immune adjuvant,particularlyin immune deficiencystates associatedwith excessiveC-AMP production. INTRODUCTION Lithium has become an importanttherapeuticmodality in the treatmentof affectivedisorders. In this Hypothesis,we propose that lithiummay prove to be an importantnew form of therapy for certain immune deficiency states. Althoughits exact mode of action on the centralnervous system is not known, lithium has been shown to interferewith a variety of adenylate cyclasesystems (1). The occasionaldeveloInnent of goiter or hypothrroidism in patientsreceivinglithiumhas been related to an inhibition of TSH-mediatedadenylatecyclaseactivationin the thyroid cell (2), or to interferencewith post-cyclicAMP events (3). Similarly,the polyuria and decreasedability to concentrateurine associatedwith lithium therapy has been attributed,at least in part, to en inhibitionof AI&mediated cyclic AMP accumulationin renal tubular cells (4). In additionto inhibitingTSH and ADH-mediatedevents,lithium also has been found to inhibit adenylatecyclaseactivationby epinephrine,fluorideand ACTH in fat cells (5-6) , and prostaglandinEl-mediatedactivationof sdenylate cyclase in platelets(7).
The activitiesof lymphocytes,macrophagesand polymorphonuclear cells can be regulatedby alterationsin cyclic nucleotidelevels. Agents which increase cellularC-AMP usually decreaseinflammatorycell numbers, cell function,and cell product synthesisand release (8-9). An increasein lymphocyteC-AMP is associatedwith decreasedproliferationto mitogenic stimulation(lo), decreasedE-rosetteformationand stability(ll), increased suppressorcell activity (12), decreasedantibodyrelease (13), and diminishedlymphokineproduction(14). An increasein C-AMP affects monocyte-macrophage by diminishedmaturationof precursorcells (is), reduced release of acid hydrolasesand decreasedtumoricidalactivity (16). Elevationsof C-AMP affect polymorphonuclear leukocytesby decreasedmaturation of bone marrow precursors(15), reduced locomotion(lb), decreased responseto chemotactic-stimuli, d&&&hed release of acid-hydrolases (18), and suppressedsuperoxideproductionand chemoluminescent activity (19)
l
In view of these diverse inhibitoryeffects of C-AMP on immune function, it occurredto us that the lithium ion, by decreasingadenylatecyclase activityand thereby lowering intracellularC-AMP levels, may stimulate lymphocytes,macrophagesand polymorphonucleer leukocytes,and thereby act as an immune adjuvant. To test tNs hypothesis,we began by examining the -in vitro effects of lithium on several indices of cellularimmunity. EFFECTS OF LITHIUM ON LYMPHOCYTES
Figure 1: Effect of lithium on mitogenicresponseto
0-I 0
12
3
4
5
LITHIUMCONCENTRATION(mEp/Ll
As shown in Figure 1, the mitogenicresponse of human mononuclearcell preparationsto PHA was enhancedprogressivelyby lithium concentrations of 0.15 to 5 mEq/L(20). In mononuclearcell preparationsnot stimulated by PHA, lithium was not itself mitogenic. ProstaglendinEl, a potent stimulatorof adenylatecyclase,significantlyinhibitedthe responseto PHA. 2
The additionof lithium at a concentrationof as little as I.25 mEq/L reversed the inhibitoryeffect of theophyllineon PHA-indexedtx%.nsformation* These observationssupport the view that lithiummay be acting on mononuclear cells by inhibitingadenylatecyclaseactivity,and thereby enhancing their function. C-AMP is known to regulaterosette formationby T cells, and if lithium is indeed acting to decreasecyclic AMP levels, one would anticipatethat lithium should increasethe ability of lymphocytesto form rosetteswith sheep erythrocytes. Our studieshave shown that this is indeed so. Ikeincubationof lymphocytesfor two hours with lithium, 1 a, increased the number of rosette-formingcells signifi.cantly (20). Our observations on the effects of lithium on mitogenicresponseof lymphocytesand on rosette formationhave been recently confirmedby Others (21). Our current studiesfurther indicatesthat lithiummay be acting,at least in part, by inhibitingthe activityof suppressorcells (22). Other investigatorshave demonstratedenhanced-in vitro antibodyproductionby lymphocytesfrom selectedpatientswith agammaglobulinemia thought to be mediated by excessivesuppressorcell activity (12). In additionto these stimulatory_in vitro effects of lithium,we have found in preliminarystudies that mice receivinga lithium-supplemented diet, who axe challengedwith sheep erythrocytes,demonstrateenhanceddelayed hypersensitivity as measured by foot pad swelling. EFFECTSON MACROPHAGES We have also demonstratedthat lithium enhancesmacrophagesphagocytosis (20). Monocyteswere isolatedfrom peripheralblood incubatedfor 3 days in media containingvarious concentrationsof lithium. They were subsequently assayed for their ability to ingest technetium-labelled latex particles. With increasingconcentrationsof lithium,phagocytosisprogressivelyrose (Figure2). Of note is the significantenhancementof phagocyt.osis at low concentrationsof lithium,well within the therapeutic plasma levels achievedin patientsreceivinglithium for treatment of affectivedisorders. d
180-
Figure 2: Effect of lithium on phagocytosis by macrophages, as assessedby the ingestionof 99Tc-labeledlatex particles. 2 LITHIUM
4
6
CONCENTRATION
8
IO l mEq / L)
EF'F'ECTS ONPOLYMORPHONUCLMAHLEUKOCYTES Lithium administrationis known to cause neutrophilia,and this property has led to the use of lithium in patientswith chemotherapy-induced neutropenia (23). Lithium is thought to increasethe neutrophilcount by enhancingthe productionof colony-stimulating activity. In preliminary in vitro studies,Perez et al have found that lithium does not enhance -random migration,chemotaxisor enzyme release of normal IWN's. One patient, however, was found to have deficientPMN functionwhich was improved by lithium (25). This patient was a 29 year old woman with a long history of eczema and recurrentstaphylococcalend streptococcal skin infections. The only discernibleabnormalitywas completeunresponsivenessof her polymorphonuclearleukocytesto standardchemotactic stimuli. The -in vitro additionof lithium to PMN preparationsrestored the previouslydeficientchemotacticresponse,and this promptedus to treat the patient with lithium. After receivinglithium carbonate,1 gm/day for 5 weeks, the chemotacticresponsivenessof her PMN*s was found to be normal, and coincidentallyshe became free of infection. Subsequent withdrawalof lithium therapy resultedin a clinicalrelapse and return to the chemotacticabmonnality. The patient has been restartedon lithium therapy,and remains well. CONCLUSION Our observationsthat lithium enhancesa variety of -in vitro indices of immune responsesraises the possibilitythat lithiummay have therapeutic potentialin selectedpatients with immune deficiencies. Lithium may find particularapplicationin patients with abnormalitiesof lymphocyte, macrophageor polymorphonuclearleukocytefunctionrelated to elevated levels of C-AMP. An example of such an immune deficiencystate may be the depressedcellularimmunity of Hodgkin'sdfsease. A prostaglandin E2-producingsuppressorcell has been identifiedin some patients with The hyporesponsiveness to PHA in these patients Hodgkin'sdisease (26). can be reversedby indomethacin,a prostaglandin-synthetase inhibitor. Pros&la&in E may act to inhibitPHA responsivenessby activating adenylatecyclase and elevatingC-AMP levels. Our -in vitro studies have shown that lithium can reverse the inhibitoryeffects of PCE (20). To explorethe possible therapeuticimplicationsof these observations, we have begun to study the effects of lithium on the mitogenicresponses of patients with Hodgkin'sdisease. Our early studiesreveal that lithium, like indomethacin,improvesthe -in vitro responsesof some patisnts. Prostsglandinsof the E series have also been shown to inhibit the activity of interferon-activated macrophsgesof mice and to reduce their tumoricidalfunction in a MBL-2 lymphoblasticleukemiacell system (16). It would be of great interestto determinewhether lithium can reverse the inhibitoryeffects of PCE in such a system. If so, such an observation may suggest a possibletherapeuticapplicationfor lithium as an adjuvant of tumor immunity. Our findingsto date thereforesuggest that lithiummay prove to have potentialtherapeuticusefulnessin selectedpatientswith abnormalities 4
of lymphocyte,macrophageor polymorphonuclear functionrelated to elevated levels of C-AMP. If such an abnormalitycan be shown to be corrected2 vitro by lithium,then a cautioustrial of therapymay be warrantedin selectedpatients.
1. Singer I, RotenbergD. Mechanismsof Lithium Action. N Engl J Med 289: 254, 1973. 2. Wolff J, Berens SC, Jones AB. Inhibitionof Thyrotropin-stimulated Adenyl CyclaseActivityof Beef ThyroidMembranesby Low Concentrationsof Lithium ion. BiochemBiophysRes Commun 39: 77, 1970. 3. Berens SC, BernsteinRS, Robbins J et al. AntithyroidEffects of Lithium. J Clin Invest 49: 1357, 1970. Cyclic 4. Beck N, Beck BB. Effects of Lithium on Vasopressin-dependent Ampin Rat Renal Medulla. Encocrinol97: 202, 1975. 5. BenjaminWB, Fish ST, Singer I. Insulin-inducedC-AMP-independent Phosphorylationof a Fat Cell Protein:Effects of Starvingand Refeeding. BiochemSOC Tram 2r 920, 1974. 6. BirnbaumerL, Pohl SL, RodbellM. Adenyl Cyclase in Fat Cells. J Biol Chem 244s 3468, 1969. 7. Murphy DL, DonnellyBS, MoskonitzJ. Inhibitionby Lithium of ProstaglandinE1 and NorepinephrineEffects on Cyclic Adenosine MonophosphateProductionin Human Platelets. Clin Pharmacol Ther 14: 810, 1973. 8. Bourne HR, LichtensteinL&l,Melmon EL et al. Modulationof Inflammation and Immunityby Cyclic AMP. Science 184: 19, 1974. 9. GoldbergND. Cyclic Nucleotidesand Cell Function:in "CellMembranes, Biochemistry,Cell Biology and Pathology",p. 185. (WeissmanG, ClairborneR, eds). H P PublishingCo, 1975. 10. HirschhornR, GrossmanJ, WeissmanG. Effect of Cyclic 3', 5'-adenosine Monophosphateand Theophyllineon LymphocyteTransformation. Proc SOC Exp Biol Med 133: 1361, 1970. Il. ChisariFV, EdgingtonIS. Human T Lymphocyte“E" Rosette Function. I A ProcessModulatedby IntracellularCyclic AMP. J Exp Med 140: 1122, 1974. 12. Dosch H, GelfandEW. FunctionalMfferentiation of B Lymphocytesin Agammaglobulinemia.III Characterization of SpontaneousCell Activity. J 1mm~n0l 12ir 2097, 1978.
5
13. Eburne HR, Melman KL, WeinsteinY et al. In "CyclicAMP, Cell Growth and The Immune Response." (Braun W, LichtensteinIM, Parker CW, eds). New York, Springer-Verlag,1974. 14. LomnitserR, Rabson AR, KoornhogHJ. The Effects of Cyclic AMP on LeucocyteInhibitoryFactor (LIF) Productionand on the Inhibition of LeucocyteMigration. Clin Exp Immunol 24: 42, 1976. 15. Kurland J, Moore AS. The RegulatoryRole of the Macrophagein Normal and NeoplasticHemopoiesis. ExperimentalHematologyToday, p. 51. (Baum S, Ledney GD, eds). New York, Springer-Verlag,1977. 16. SchultzeRM, PavlidisNA, Stylos WA et al. Regulationof Macrophage TumoricidalFunction:A Role for Prostaglandinsof the E Series. Science 202: 320, 1978. 17. Tse RL, Phelps P, Urban D. Polymorphonuclear LeukocyteMobility in vitro VI. Effect of Purine and PyrimidineAnalogues:Possible Role of Cyclic AMP. 18. WeissmanG, Dukor P, Zurier RB. Effect of Cyclic AMP on the Release of LysosomalEnmymes from Phagocytes. Nature (London)New Biol 231: 131, 1971. Drugs and 19. LehmeyerJE, JohnstonJr AB. Effect of Anti-Inflammatory Agents that Elevate IntracellularCyclic AMP on the Release of Toxfc Oxygen Metabolitesby Phagocytes:Studies in a Model of Tissue-BoundIgG. Clin Immunol Immunopath9: 482, 1978. 20. ShenkmanL, Borkowsb W, Holmman RS et al. Enchancementof Lymphocyte and MacrophageFunction in vitro by Lithium Chloride. Clin Immunol Immunopathol10: 187, 1978. 21. Gelfend EW, Dosch H, HastingsD et al. Lithium:A Modulatorof Cyclic AMP-Dependenthrents in Lymphocytes? Science 203: 365, 1979. 22. Wadler S, Shenkman L, BorkowsIqW. Effects of Lithium on SuppressorEnriched and Suppressor-Depleted MononuclearCell Preparations. Clin Res 27: 339, 1979. 23. Stein RS, Beeman C, Ali MY et al. Lithium CarbonateAttenuationof Chemotherapy-Induced Neutropenia. New Engl J Med 297: 430, 1977. 24. Harker WG, RothsteinG, ClarksonD et al. Enhancementof ColonyStimulatingActivityProductionby Lithium. Blood 49: 263, 1977. 25. Peres HD, Kaplan H, ShenIenan L et al. Reversal of an Abmonnalityof Polymorphonuclear LeukocyteChemotaxiswith Lithium. Clinical Res 27: 353, 1979. 26. Good- JS, Messner RP, BankhurstAD et al. Prostaglandin-Producing SuppressorCells in Hodgkin'sDisease. New Engl J Med 297: 963, 1977. 6