Type Hypersensitivity Response in Mice

[CANCER RESEARCH 43, 3514-3518, September 1982]

Enhancing Activity of Various Immunoaugmenting Agents on the Delayed- Type Hypersensitivity Response in Mice

Anna Bartocci, Elizabeth L. Read, Roy D. Welker,1 Erich Schlick,2 Vasilios Papademetriou, and Michael A. Chingos '

Laboratory ol Chemical Pharmacology, National Cancer Institute, NIH, Bethesda, Mary/and 20205

ABSTRACT have been reported to have an effect on one or more cellular elements of the immune system (1, 3-6). Since the DTH Six immunoaugmenting agents were tested in the delayed- response is a measure of both macrophage and T-cell inter type hypersensitivity reaction (DTH) in normal BALB/c x DBA/ action, it was of interest to assess whether a correlation exists 2 mice. The agents tested, levan, lentinan, mannozym, maleic between the capacity of selected agents which enhance mac anhydride divinyl ether, polyriboinosinic-polycytidylic acid- rophage and/or NK cell activity and their ability to effect the poly-L-lysine, and highly purified L-cell interferon, gave signifi DTH response. The role of the macrophage in the DTH re cant increases in the DTH response above the sheep red blood sponse would be determined by using CARR to suppress cell control. The schedule of doses for each agent corre macrophages (2, 24, 32). sponded with previous experiments from this laboratory of the This report presents the results of testing 3 polysaccharides maximum natural killer cell activity, macrophage activation, and (levan, lentinan, mannozym), 2 chemicals (poly ICLC, MVE-2), interferon induction. Highly purified L-cell interferon was ca and IF for their capacity to enhance the DTH response to SRBC pable of eliciting a significant DTH response when given 4 hr and to overcome CARR-induced suppression of this response. after the initial challenge with sheep erythrocytes. In addition, A-carrageenan, a macrophage-cytotoxic agent which can ren MATERIALS AND METHODS der the macrophage inactive, was found to suppress the DTH response to levels slightly above phosphate-buffered saline Animals. Adult male 6- to 8-week-old BALB/c x DBA/2 (hereafter controls. The carrageenan-induced suppression of the DTH called CD2F,) weighing approximately 25 g were supplied by the response could be abrogated by coadministration with immu Mammalian Genetics and Animal Production Section, Drug Research noaugmenting agents to levels attained with the immunoaug and Development, National Cancer Institute, NIH, Bethesda, Md. Mice menting agents alone. were housed in plastic cages with air filter bonnets and fed Purina laboratory chow and water ad libitum. Drugs. Levan, a polysaccharide extracted from the cell wall of INTRODUCTION Aerobacter levan, was generously supplied by Dr. M. Walman, Depart The DTH" response is considered to result from interaction ment of Pathology, Tel Aviv University Medical School, Tel Aviv, Israel. Lentinan, a /?-1,3-glucan obtained from the mushroom Lentinan in vivo between macrophages presenting foreign antigens to edodes, was a gift from Dr. Yasumi Yugari of the Life Science Labo the T-cells. Macrophages can also effect T-cell function in the ratory, Ajinomoto Company, Yokohoma, Japan. Mannozym, a gluco- DTH response by releasing soluble factors that enhance de mannan polysaccharide purified from Saccharomyces cerevisiae, was velopment of precursor cells into effector T-cells. generously provided by Dr. Pierre Jacques, BiomÃ©dical Cytology, In the final step(s), the lymphokines formed by the antigen- Centre Interuniversitaire de Recherches Multidisciplinaires en Affec tions Parasitaires et Mecanisms de Defense de l'HÃ´te, Brussels, Bel stimulated T-cell activate the macrophages which participate in the DTH response (13, 20, 23). The histological evidence gium. Levan, lentinan, and mannozym were tested for the presence of endotoxin, and none could be detected (14). MVE-2 was supplied by for the presence of mononuclear cell infiltration (primarily lym Dr. Richard Carrano, Adria Laboratories, Columbus, Ohio. Poly ICLC phocytes and macrophages) at the site of challenge supports stabilized with carboxymethylcellulose was obtained from Dr. Hilton the fact that both lymphocytes and macrophages participate in Levy, Molecular Virology Section, National Institute of Allergy and the DTH response (9). Infectious Diseases, NIH, Bethesda, Md. Highly purified mouse L-cell Several agents have been reported to exert a regulatory IF was purchased from Dr. Kurt Paucker, University of Pennsylvania effect on various cellular components of the immune system. Medical School, Philadelphia, Pa. CARR was purchased from Sigma IPs have been reported to increase phagocytosis (15), enhance Chemical Company, St. Louis, Mo., and was dissolved in PBS by macrophage tumoricidal activity (25), and augment NK cell heating for 10 min. activity (11, 12, 31). Type I IF has also been described as DTH Assay. Fresh sheep erythrocytes purchased from Flow Labo influencing cell-mediated immunity (8) and the afferent (9, 10) ratories, McLean, Va., were washed 3 times in PBS and diluted to 2 x 109 cells/ml. The left rear footpad of CD2F! mice was given i.d. and efferent (8) pathways of the DTH response. Other agents injections of 0.05 ml of the SRBC suspension on Day 0. On Day 5, 0.05 ml of SRBC at 2.0 x 109 cells/ml was injected i.d. into the right ' Present address: Litton Bionetics. Inc.. Kensington, Md. 20795. rear footpad. Three measurements of each rear footpad were taken 2 Supported by Deutsche Krebshilfe e.V.. 5300 Bonn, Federal Republic of with a gravity-sensitive calibrated measuring device on Day 5. The Germany. 3 To whom requests for reprints should be addressed. difference in footpad swelling between the right (sensitized) rear and ' The abbreviations used are: DTH. delayed-type hypersensitivity; IF. inter left rear footpad was recorded as the individual DTH response. Each feron; NK, natural killer; CARR, A-carrageenan; poly ICLC, polyriboinosinic- experimental group contained 8 mice. A PBS (negative) control and a polycytidylic acid poly-L-lysine; MVE-2, maleic anhydride divinyl ether; SRBC, sheep red blood cells; i.d.. intradermally: PBS, phosphate-buffered saline. SRBC (positive) control were also included in each experiment. The Received August 17, 1981; accepted May 28. 1982. standard deviation within each group never exceeded Â±0.03 mm.

3514 CANCER RESEARCH VOL. 42

Significant values for the experimental groups were obtained by using after injection, for mannozym and MVE-2 at 3 days, and for the Student's t test. poly ICLC at 1 day. Macrophage Activation Assay. The assay for measuring the ability The most significant augmentation of NK cell activity paral of agents to induce macrophage-mediated cytotoxicity has been de leled the same time as that observed on macrophage activation scribed previously (27). Briefly, 6- to 8-week-old BALB/c mice re for mannozym, MVE-2, and poly(ICLC). However, the peak of ceived a single i.p. treatment of drugs or PBS. Peritoneal macrophages were harvested, adjusted to 8.0 x 105 macrophages per ml in Roswell NK cell activity for levan and lentinan occurred 3 days prior to their peak of macrophage activation. Park Memorial Institute Medium 1640 supplemented with 10% fetal calf serum and 125 /Â¿ggentamicin per ml, and allowed to adhere for 2 DTH Response. The test agents were examined for their hr in 16-mm wells (tissue culture cluster plate; Costar, Cambridge, capacity to enhance the DTH response. Each agent was ad Mass.). After a washing to remove nonadherent cells, the macrophage ministered at various times prior to the initial SRBC sensitization monolayers were overlaid with MBL-2 leukemia cells adjusted to 8.0 (Table 2). The results of several tests show that each agent x 10" cells/ml. All cultures were maintained in a humidified incubator significantly enhanced the DTH response in a dose-dependent with 5% CO2:air at 37Â°. Viable MBL-2 cells were counted in a hemo- manner (Table 3). Optimum activity for each agent was cytometer after 48 hr. Percentage of growth inhibition of MBL-2 cells achieved when it was administered at the same time found to due to macrophage activation was calculated by comparison to MBL- give maximum macrophage activity. 2 cells grown in the presence of normal control macrophages. NK Cell Assay. A conventional 5'Cr release assay was used as Since poly ICLC was the most effective in enhancing both described previously by others (16). In brief, 2.0 x 10" radiolabeled the macrophage and NK cell activity as well as being the most YAC-1 (7) target cells (100 Â¿iCiof 51Cr; specific activity, 250 to 800 effective inducer of IF (3, 5, 21), this agent was studied more mCi/mg/1.0 x 107 tumor cells at 37Â° for 45 min) in 0.1 ml volume were added to graded numbers of splenic effector cells (final effec- Table 2 tortarget ratios were 200:1, 100:1, 50:1, or 25:1 ) in round bottomed DTH response after treatment in vivo with immunoaugmenting agents at 96-well microtiter plates. The final volume was 0.2 ml/well. Triplicate different times cultures were maintained in a humidified, 5% CO2:air incubator at 37Â° The values are compared to the SRBC control. Mice received a single i.p. for 4 hr. The plates were then centrifuged for 10 min at 800 x g, and injection. PBS control, 0.02 Â±0.005; SRBC control, 0.19 Â±0.02. a volume of 0.1 ml of supernatant was removed and measured in a Mean increase in tootpad swelling (mm) gamma counter. Spontaneous release was determined by incubation of 2.0 x 10" tumor cells in 0.2 ml of Roswell Park Memorial Institute Â±0.02a- " Â±0.01b Â±0.01 c Levan (50 mg/kg) Medium 1640 supplemented with 10% fetal calf serum and 125 fig 0.53 Â±0.02Â° 0.28 Â±0.02fi 0.25 Â±0.01Â° Lentinan (100 mg/kg) 0.42 Â±0.03Ã– 0.27 Â±0.01 Â° gentamicin per ml. Maximum release of radioactivity was determined Mannozym (4 mg/kg) 0.18 Â±0.01 by freezing and thawing of 2.0 x 104 tumor cells 4 times in an 0.54 Â±0.026Day-10.240.26 Â±0.01 c MVE-2 (25 mg/kg)Day-60.48 0.18 Â±0.02Day-30.28 acetone:dry ice bath. Maximum release of radioactivity varied from 85 Mean Â±S.E. of 3 experiments (n = 8). to 95% of total isotope uptake, and spontaneous release varied from bp< 0.001. 7 to 12% of maximum release. The percentage of cytotoxicity was cp<0.01. calculated from the formula: Experimental cpm - Table 3 Dose response by various immunoaugmenting agents on DTH response spontaneous release cpm % of cytotoxicity =- x 100 Day of Mean increase maximum release cpm treat- Â¡nfootpad - spontaneous release cpm Agent Dose ment swelling (mm) p Â±0.05a0.46 IFLevanLentinanMannozymMVE-2Polyx 106units/mouse1 x 105units/mouse5 Â±0.030.34 RESULTS x 105units/mouse1 1-1-6-6-6-6-6-6-6-6-3-3-3-3-3-3-3-3-1-1-1-10.29Â±0.020.24 x 10'units/mouse100 Â±0.040.30 Effect of Test Agents on Macrophage and NK Cell Activity. All the agents were found to be effective in enhancing macro mg/kg50 Â±0.010.49 mg/kg20 Â±0.020.28 phage tumoricidal activity (Table 1). The optimum response mg/kg10 Â±0.010.21 occurred at different time intervals after injection of test agent. mg/kg200 Â±0.020.43 The peak of activity for levan and lentinan occurred at 6 days mg/kg100 Â±0.030.53 mg/kg50 Â±0.020.31 Table 1 mg/kg10 Â±0.010.21 Macrophages and NK activity after treatment in vivo with immunoaugmenting mg/kg8 Â±0.020.34 agents at different times mg/kg4 Â±0.050.43 1Levan Day 6NKa7.48.5753Macro mg/kg2 Â±0.040.23 mg/kg1 Â±0.030.20 phage6681795Ã–93"50eDayphage681e65209130 mg/kg50 Â±0.030.45

mg/kg25 Â±0.040.54 (50mg/kg)Lentinan mg/kg10 Â±0.020.35 mg/kg)Mannozym(100 mg/kg5 Â±0.030.28 mg/kg)MVE-2(4 mg/kg6 Â±0.010.25 mg/kg)Poly(25 ICLC (4 mg/kg)NKa898250"Macro-phage66337161574dDay3NKa12.511.225C15C20CMacro ICLC1 mg/kg4 Â±0.050.50 NK activity, % of cytotoxicity above controls inoculated with PBS; target mg/kg2 Â±0.030.24 cens, YAC-1 ; Effector target cell ratio, 100:1. mg/kg1 Â±0.080.22 Macrophage tumoricidal activity. % of inhibition of MBL-2 leukemic cell mg/kg-1-1â€” Â±0.03<0.01<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.002<0.001<0.001<0.001<0.002<0.01<0.05<0.001<0.05 growth. Mean Â±S.E. of 3 experiments (n = 8). Values are compared to the SRBC cp< 0.002. d p< 0.001. control. Mice received a single i.p. injection. PBS control. 0.02 Â±0.005; SRBC control, 0.02 Â±0.001.

SEPTEMBER 1982 3515

extensively (Chart 1). Significant enhancement of the DTH on the day which produced maximum activity (levan, lentinan, response occurred when poly ICLC was administered as early Day -6; mannozym, MVE-2, Day -3; and poly ICLC, Day -1). as 3 days before and at the time of the initial injection with All of these injections were given prior to the initial challenge SRBC. The most significant enhancement occurred when it with SRBC. All 5 agents effectively reversed the depression of was given 1 day prior to sensitization. These results correlate the DTH response induced by CARR treatment (Chart 2). MVE- well with its optimal effect on macrophage and NK cell response 2 and poly ICLC appeared to be the most effective since they (Table 1). However, if poly ICLC was administered after the gave a response higher than the SRBC control value alone. initial SRBC sensitization, no effect was seen except when the Results in Chart 3 show the mean of the responses of mice drug was given on the third day after initial sensitization and a when IF was tested for its capacity to reverse CARR depression significant depression on the DTH was observed. of the DTH response. CARR administered 2 days prior to SRBC Depression of the OTH Response by CARR. Various con sensitization depressed the response from the SRBC control centrations of CARR have been reported to be capable of value of 0.25 to 0.05 mm. IF alone, when administered 4 hr depressing the DTH response. First, it was necessary to deter after sensitization, significantly enhanced the DTH response to mine the maximum tolerated dose of CARR. Mice were given a value of 0.42 mm. IF was found to be capable of reversing i.p. injections of a single dose of CARR ranging from 2 to 40 mg/kg. Mice tolerated the 20-mg/kg dose well. Doses greater U.rju|o.50f10.401| than 32 mg/kg result in anorexia and early death. Results in Table 4 show that at the 20-mg/kg CARR dose the maximum depression of the DTH response occurred when administered 2 days prior to SRBC sensitization. When CARR was adminis tered 1 or 2 days after sensitization, little or no depressive Ia Ã¯0Â£T_"*!Ã± i effect was observed. Â°-30.SÂ¡0.201 Capacity of Test Agents to Restore CARR Depression of the DTH Response. CARR was injected on the day of its most suppressive effect (Day â€”2),and the test agents were given

0.100.08ciX.Â§0i

0.50 CarrageenanCarrageenanCarrageenanCrrageenanCarragaenanCarrageenÂ«!nTTfrTÂ£'â€¢*â€¢ o V Control Control + + levan laminan Mmoiym MÃ®t2 My ICIC

0.40 Chart 2. Capacity of test agents to restore CARR depression of the DTH response. CARR was administered 2 days prior to initial SRBC sensitization. Test agents were administered at the time periods previously found to be optimal for macrophage and NK cell activity. Day -6: levan, 50 mg/kg; lentinan, 100 mg/ kg; Day -3: mannozym, 4 mg/kg; MVE-2, 25 mg/kg; and Day -1: poly ICLC, ! z 0.30 4 mg/kg. Results are expressed as the mean of 5 separate experiments; bars, S.E. Values are compared to the group treated with CARR alone.

Ã•< 0.20 o V 0.40OJO0.200.10n -r'"*!P< < 0.001

0.1II

111] PBS SRBC Day 3 Day-2 Day-1 Day 0 Day 1 Day 2 Day 3 CONTROL CONTROL 1-DAY OF ADMINISTRATION OF POLY ICLC-I (4mg/kg) Chart 1. Effect of a single injection of poly ICLC (4 mg/kg) administered at different time intervals in relation to the initial SRBC sensitization. Results are the mean of 3 experiments: bars, S.E.

Table 4 Depression of DTH response by CARR administered at different time periods 0.001Ã±-i-â€”I---PBS (mg/ increase in foot SRBC"Day kg)2020202020Day-2-1012Mean pad swelling(mm)0.22 60.10Â±0.01 0Day 0Day Â±0.010.11 fi-ip 0Day Â±0.020.13 SRBC SRBC SRBC SRBC CONTROL CONTROL + -I-CARR-HF +IF 0Day Â±0.010.19 CARR 0DayOCARR Â±0.010.22 Â±0.02 Chart 3. Capacity of IF to restore CARR depression on the DTH response. " DTH response conducted according to assay described in "Materials and CARR (20 mg/kg) was administered 2 days before, and IF (1 x 10s units/ Methods." mouse) was administered 4 hr after the initial SRBC sensitization. Results are Mean Â±S.E. expressed as the mean of 4 separate experiments; bars, S.E.

3516 CANCER RESEARCH VOL. 42

the CARR-induced depression attaining a value of 0.40 mm, able to maintain their capacity to respond to the SRBC and close to that achieved when IF alone was used. may be less susceptible to the action of CARR. It also seems very possible that a second population of macrophages not DISCUSSION damaged in their function by CARR can be reactive as shown by the restoration of the DTH response with poly ICLC and IF, All 5 agents examined (levan, lentinan, mannozym, MVE-2, which are injected after CARR. Finally, we cannot exclude the and poly ICLC) were shown to enhance markedly the response fact that IF alone acts directly as a messenger on the T cells of macrophages and NK cells. Using the same time sequence responding to the antigen in the DTH response, thus overcom found optimal for each agent to stimulate macrophage activa ing the suppressive properties of CARR. The enhanced DTH tion, all 5 drugs also significantly enhanced the DTH response. response obtained with the 6 Â¡mmunoaugmenting agents cor Several studies show that IF plays a regulatory role in macro related well with their capacity to regulate macrophage and NK phage enhancement (26, 28) and NK cell augmentation (11, cell activity. This DTH assay could serve as an additional cell- 12, 31) and, indeed, indicate that IF is the primary signal for mediated assay for evaluating potential immunoaugmenting regulation of these cellular elements of the immune system. IF, agents. when injected exogenously or induced endogenously by New castle Disease Virus, has been reported to play a regulatory ACKNOWLEDGMENTS role in the DTH response (9, 10). These reports demonstrated that IF exerted a modulatory effect on DTH, inhibiting or en We gratefully acknowledge M. R. Mitchell for her excellent technical assist hancing the response in relation to the time of injection. Optimal ance and C. Bower for her excellent secretarial assistance. enhancement with IF occurred when it was injected 4 hr after primary sensitization with SRBC. Results of the present study show that a dose-dependent REFERENCES enhancement of the DTH with levan, lentinan, mannozym, MVE- 1. Bartocci, A., Papademetriou, V., and Chingos, M. A. Enhanced macrophage and natural killer cell antitumor activity by various molecular weight maleic 2, and poly ICLC occurred when they were administered before anhydride-divinyl ethers. J. Immunopharmacol., 2: 149-158, 1980. the primary sensitization with the antigen. It was of interest to 2. Bice, D. E., Gruwell, D. G., Salvaggio, J. E., and Hoffman, E. O. Suppression speculate whether the enhanced DTH response achieved with of primary immunization by carrageenan. A macrophage toxic agent. Im- munol. Commun., 1: 615-625, 1972. these drugs could be due to IF induction and/or due to their 3. Chirigos, M. A., and Jacques, P. 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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1982 American Association for Cancer Research. Enhancing Activity of Various Immunoaugmenting Agents on the Delayed-Type Hypersensitivity Response in Mice

Anna Bartocci, Elizabeth L. Read, Roy D. Welker, et al.

Cancer Res 1982;42:3514-3518.

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