Reduction of Contact Sensitivity Reactions to Oxazolone in Mite-Infested Mice

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INFECTION AND IMMUNITY, Oct. 1979, p. 30-35 0019-9567/79/10-0030/06$02.00/0 Vol. 26, No. 1 Reduction of Contct Sensitivity Rections to Oxzolone in Mite-Infested Mice HANS LALTOO AND LEON S.

1 INFECTION AND IMMUNITY, Oct. 1979, p /79/ /06$02.00/0 Vol. 26, No. 1 Reduction of Contct Sensitivity Rections to Oxzolone in Mite-Infested Mice HANS LALTOO AND LEON S. KIND* Microbiology Deprtment, Fculty ofmedicine, Dlhousie University, Hlifx, Nov Scoti, Cnd Received for publiction 22 September 1978 Oxzolone-sensitized mite-infested (SWR-M) nd mite-free (SWR-J) mice were chllenged with oxzolone on the skin of the neck nd shoulder. The migrtion of rdioctively lbeled cells to the site of contct sensitivity rection to oxzolone ws significntly less in SWR-M thn in SWR-J mice. Serum obtined from SWR-M mice suppressed the extrvstion of cells into the skin site of SWR-J mice chllenged with oxzolone. The decrese in cellulr influx in SWR-M mice occurred in res of mite infesttion (skin of neck nd shoulder) s well s in res not infested with mites (the ers). SWR-M mice lso gve evidence of enhnced vsculr permebility. A possible role for histmine in the inhibition of contct sensitivity in mite-infested mice is discussed. The induction s well s the regultion of prsitic nd other chronic infections often hve n immunologicl bsis. The schistosome-infected mouse (4, 14, 15, 26) s well s mice infested with Trichinell spirlis (2, 3, 13, 23) hve proven to be especilly useful in studies concerned with immunoregultion in chronic disese. In schistosomisis of mice, for exmple, depression of response to the T cell mitogens concnvlin A nd phytohemgglutinin hs been demonstrted (14). Spleen cells from Schistosomisis mnsoni-infected mice were shown to inhibit the cell-medited immune response of norml spleen cells to llogeneic cells (4). With regrd to mite infesttions, it hs been shown tht dogs with severe mnge due to the mite Demodex cnis showed depression of T cell function in tht their lymphocytes did not respond to mitogenic concentrtion of phytohemgglutinin. T cell suppression ws corrected by destruction of the mites. The serum of miteinfested dogs ws shown to suppress the phytohemgglutinin-induced prolifertion of lymphocytes obtined from mite-free dogs (22). The purpose of our experiments ws to study immune regultion in mild, chronic mite infesttion of mice. We recently reported tht mice infested t birth or s dults with the mouse mite Myocoptes musculinus develop positive skin tests to mite ntigens s well s high, persistent levels of immunoglobulin E nti-mite ntibodies in their serum (7). The plcement of mite extrct in connective tissue ir pouches in the skin of mite-infested mice resulted in extensive mst cell degrnultion (7). Mite infesttion is lifelong if the nimls re untreted (29), nd infested mice re undoubtedly subjected to continul ntigenic stimultion nd meditor relese (histmine, etc.). The dt which follow indicte tht the extrvstion of rdioctively lbeled cells into the site of contct sensitivity rections is significntly reduced in mice mildly infested with mites. In ddition, the serum of mite-infested mice is shown to be cpble of cusing this nonspecific reduction in cellulr influx. MATERIALS AND METHODS Mice. Mle nd femle, 8- to 12-week-old, miteinfested SWR mice (SWR-M) were employed in our experiments s well s noninfested SWR mice purchsed from Jckson Lbortories, Br Hrbor, Me. (SWR-J). Mite infesttion ws determined by exmining the skin surfce (under Nembutl nesthesi) with stereomicroscope t 30x mgnifiction. We hve rbitrrily clssified the severity of mite infesttion from 1+ to 4+ on the bsis of the following criteri: cot norml, but mites present, 1+; shggy cot, 2+; slight loss of hir round hed nd shoulders with reddening of skin (mnge), 3+; extensive loss of hir in lrge ptches, infection, 4+. The mice used in the experiments to be described were grded s 1+ (see Fig. 1). Mst cell distribution in mouse skin. Gershon et l. (5) demonstrted tht comprison of mst cell concentrtion in different skin sites of the mouse could be mde by the locliztion of injected serotonin binoxlte ([3H]5HT) fter injecting mice with 6-hydroxydopmine to prevent the uptke of [3H]5HT by drenergic nerves. They exmined skin sections by utordiogrphy nd found rdioctive serotonin only in mst cells. Using the method of Gershon et l. (5), we determined the [3H]5HT uptke in the ers nd in the neck nd flnk skin of SWR-M nd SWR-J mice fter they were injected intrvenously (i.v.) with 0.1 mci of tritited 5HT. 30

The er is most often used s the chllenge site in contct sensitivity rections. The ers of mice re free of mites even when the neck nd suprscpulr res re hevily infested (29).

2 VOL. 26, 1979 Delyed hypersensitivity rections (DTH) in mouse skin. SWR-M nd SWR-J mice were sensitized by the ppliction of 0.1 ml of 3% oxzolone in ethnol to the skin of the clipped bdomen nd were chllenged 7 dys lter' with 2% oxzolone in olive oil (1). The site of chllenge ws the skin of the neck nd suprscpulr region. The er is most often used s the chllenge site in contct sensitivity rections. The ers of mice re free of mites even when the neck nd suprscpulr res re hevily infested (29). It therefore seemed of interest to use both res s sites for contct sensitivity rections. Mesurement of contct sensitivity ws crried out by two different procedures: one depends on locliztion of nonimmune 61Cr-lbeled bone mrrow cells t the site of chllenge (20) nd the second is bsed on the incorportion of 5-iodo-2'-deoxyuridine "1I (lniudr) into mononucler cells which infiltrte the chllenge site (11, 24). Rdioctivity ws mesured in Unitron gmm counter, model Ech smple of skin ws counted for 1 min. In the 61Cr method, both oxzolone-sensitized nd nonsensitized mice were chllenged with oxzolone in the neck-suprscpulr region. The nimls were then injected i.v. with 5 x Cr-lbeled SWR bone mrrow cells. Twenty-four hours lter, the mice were killed nd piece of skin from the chllenged site (11 mm in dimeter) ws excised with punch. The rtio of counts per minute in the skins of sensitized nd nonsensitized mice ws determined. In the l"iudr method, sensitized nd nonsensitized nimls were chllenged with oxzolone s described. An i.v. pulse of InIUdR (2 ACi) ws dministered 10 h lter. Sixteen hours fter the injection of "25IUdR, neck-suprscpulr skin ws excised nd rtios of rdioctivity were determined s described for 51Cr. It should be pointed out tht no visible signs of DTH occur in the neck-suprscpulr skin of oxzolonechllenged mice. Infiltrtion of lbeled cells into this re, however, does tke plce, nd the rection stisfies the criteri of DTH with regrd to pssive trnsfer, timing (see Tbles 3 to 5), nd histology (unpublished observtion). Tests for vsculr permebility. The bcks of SWR-M nd SWR-J mice were shved. The next dy the nimls were injected i.v. with 10og of cinnmycin or 50 fig of mellitin in 0.3 ml of 0.5% Evns blue dye. Thirty minutes lter, the mice were killed by cervicl disloction nd the inside of the dorsl skin ws exmined for blueing. Both mellitin nd cinnmycin re known to be potent mst cell degrnultors (12, 21). Suppression by serum of the cellulr influx of contct sensitivity. SWR-M nd SWR-J mice (not sensitized to oxzolone) were bled from the brchil plexus, nd the respective ser were pooled. Oxzolone-sensitized SWR-J mice were chllenged with oxzolone nd immeditely fterwrds they were injected intrperitonelly with 1.0 ml of SWR-M serum or 1.0 ml of SWR-J serum. The determintion ofdth to oxzolone ws then crried out s lredy described. Chemicls. [3H]5HT (15 to 30 Ci/mmol), 125IUdR (>2,000 Ci/mmol), nd rdioctive sodium chromte were purchsed from New Englnd Nucler Corp., Montrel, Quebec. Oxzolone ws obtined from British Drug House, Toronto, Ontrio. Mellitin nd 6- MITE-INFESTED MICE 31 hydroxydopmine were purchsed from Sigm Chemicl Co., St. Louis, Mo., nd cinnmycin ws obtined through the courtesy of Odette Shotwell, U.S. Deprtment of Agriculture, Peori, Ill. RESULTS In Fig. 1B, we see the norml ppernce of the fur of the mildly infested SWR-M mice used in our experiments. The cot is very similr to tht of mite-free SWR-J mouse (Fig. 1C). A hevily infested mouse with loss of hir nd shggy cot is shown for comprison (Fig. 1A). Figure 2 demonstrtes the enhnced vsculr permebility of the skin of SWR-M mice. Incresed permebility is mde evident by the extrvstion of Evns blue dye (drk res) in the dorsl skin of mice injected i.v. with dye nd the mst cell degrnulting gent cinnmycin. The dt in Tble 1 indicte tht six out of six SWR-M mice injected with cinnmycin nd dye or mellitin nd dye demonstrted diffuse blueing of the dorsl skin wheres none of six SWR-J mice showed lekge of the dye fter the injection of microgrm doses of these gents. The likely bsis for the incresed vsculr permebility of SWR-M mice is n incresed number of mst cells in the skin of such nimls. This is mde evident in Tble 2. It cn be seen tht locliztion of injected [3H]5HT (which reflects the mst cell concentrtion of n re [5]) is significntly greter in the neck nd flnk skin of SWR-M mice thn in comprble regions of SWR-J mice. Incresed numbers of mst cells (demonstrted by microscopy of tissue sections) FIG. 1. Appernce of the cot of mouse with mild mite infesttion (B) in comprison with the cot of mite-free mouse (C) nd with the fur of hevily infested mouse (A).

32 LALTOO AND KIND INFECT. IMMUN. FIG. 2. Mrked extrvstion of Evns blue dye into the dorsl skin of mite-infested mouse (A). The niml ws injected i.v. with dose of the mst cell degrnulting gent cinnmycin (10 pg) which hd no effect in mite-free mouse (B).

3 32 LALTOO AND KIND INFECT. IMMUN. FIG. 2. Mrked extrvstion of Evns blue dye into the dorsl skin of mite-infested mouse (A). The niml ws injected i.v. with dose of the mst cell degrnulting gent cinnmycin (10 pg) which hd no effect in mite-free mouse (B). TABLE 1. Vsculr permebility to Evns blue dye in mite-infested SWR-M nd norml SWR-J mice injected with cinnmycin or mellitin Lekge of *Mst cell degrnult- dye into dor- Mice.ntcent sl skin (no. ng gent positive/totl no. injected) SWR-M Mellitin" 6/6 SWR-J Mellitin 0/6 SWR-M Cinnmycinc 6/6 SWR-J Cinnmycin 0/6 See Fig. 2. b 50ftg in 0.3 ml of 0.5% Evns blue dye dministered intrvenously. ' 10 yg in 0.3 ml of 0.5% Evns blue dye dministered intrvenously. in mite-infested res of skin hve been reported previously (18, 20). The dt in Tbles 3 to 5 confirm the findings of Vds et l. (24) nd Miller et l. (11) tht the '25IUdR method is mesure of DTH. It ws felt necessry to repet the experiments of Vds nd Miller becuse we chllenged our mice in the skin of the neck-suprscpulr region, n re in which no visible rection occurs. The rection of oxzolone-sensitized mice to chl- _i S...,.A TABLE 2. Locliztion of injected [3H]5HT t vrious skin sites in mite-infested SWR-M nd mite-free SWR-J mice [3H]5HT uptke (cpm/mg) Skin site SWR-M SWR-J Neck-suprscpulr 318"b± b ± 7.5 Flnk 200' ± c ± 3.7 Er 134d ± d ± 6.3 Mice were injected with 0.1 mci of [3H]5HT. b [3H]5HT uptke of neck-suprscpulr skin is significntly greter in SWR-M mice thn in SWR-J mice; P < c [3H]5HT uptke of flnk skin is significntly greter in SWR-M mice thn in SWR-J mice; P < d No significnt difference of [3H]5HT uptke between er of SWR-M nd SWR-J mice. lenge pinting of oxzolone ws positive t 24 h but not t 3 or 6 h (Tble 3). A mximl rection to oxzolone occurred 5 to 7 dys fter sensitiztion (Tble 4). The dt in Tble 5 demonstrte tht oxzolone sensitivity cn be doptively trnsferred by lymph node cells. The dt in Tble 6 demonstrte tht migrtion of rdioctively lbeled cells to res of skin chllenged with oxzolone is significntly less in

VOL. 26, 1979 TABLE 3. 125IUdR ssy for DTH in necksuprscpulr skin: response t vrious times fter chllenge with oxzolone Time fter chllenge SIN rtio' dose of oxzolone (h) 3 0.85 ± 0.15 6 0.76±0.19 24 1.

4 VOL. 26, 1979 TABLE IUdR ssy for DTH in necksuprscpulr skin: response t vrious times fter chllenge with oxzolone Time fter chllenge SIN rtio' dose of oxzolone (h) ± ± ± 0.25 SWR-M nd SWR-J mice were sensitized by the ppliction of 0.1 ml of 3% oxzolone in ethnol to the skin of the clipped bdomen; they were chllenged 7 dys lter in the neck-suprscpulr region with 2% oxzolone in olive oil. b Ten hours fter chllenge with oxzolone, mice were injected with 2 ILCi of '`IUdR intrvenously. Sixteen hours lter, the mice were killed nd piece of skin from the chllenge site (11 mm in dimeter) ws excised with punch. The rtio of counts per minute in the skins of sensitized nd nonsensitized mice (S/N rtio) ws then determined. TABLE 4. '25IUdR ssy for DTH in necksuprscpulr skin: DTH s function of time fter sensitiztion Dys fter sensitiztion S/N rtio to oxzolone ± ± ± ± 0.29 See footnote b, Tble 3. SWR-M thn in SWR-J mice. Two different methods, both of which hve been shown to mesure DTH (27, 28), gve the sme result. The reduction of the migrtion of rdioctively lbeled cells occurred in both the neck-suprscpulr skin re, which is mite-infested, nd in the ers, which do not contin mites. The dt in Tble 7 indicte tht serum obtined from mite-infested SWR mice contins fctor which suppresses the extrvstion of cells into the site of contct sensitivity rection to ox- MITE-INFESTED MICE 33 zolone. Serum from mite-free SWR-J mice did not possess this nonspecific suppressive mteril. DISCUSSION The mjor findings in our experiments re (i) the significnt reduction of cellulr infiltrtion in contct sensitivity rections of mite-infested (SWR-M) mice s compred with noninfested (SWR-J) mice nd (ii) the bility of serum from mite-infested mice to cuse this reduction in cellulr influx when injected into oxzolone-sensitized SWR-J mice chllenged with oxzolone in the neck-suprscpulr res. Our results not only demonstrte the usefulness of the mite-infested mouse s model for the study of immune regultion but lso suggest (lthough the evidence is dmittedly circumstntil) tht histmine my be the regultor molecule in this system. It my be reclled tht SWR-M mice showed n enhnced vsculr permebility which ws mde visible by the extrvstion of Evns blue dye into dorsl skin fter the i.v. injection of the mst cell degrnulting gents mellitin nd cinnmycin (Fig. 1, Tble 1). The enhnced vsculr permebility is likely the consequence of the TABLE IUdR ssy for DTH in necksuprscpulr skin: doptive trnsfer of sensitivity to oxzolone Recipient mice Cells trnsferred S/N rtio' P vlue SWR-J norml 2 x 10' norml 1.29 ± lymph node, i.v. <0.01 SWR-J norml 2 x 107 oxzolone 1.86 ± 0.28J sensitized lymph node, i.v.b SWR-J sensi ± 0.23 tized See footnote b, Tble 3. 'Lymph node cells from mice sensitized with oxzolone 5 dys previously. TABLE 6. Comprison of contct sensitivity rection to oxzolone in the neck-suprscpulr skin nd in the ers of mite-infested SWR-M nd norml SWR-J mice S/N rtio Expt Site of chllenge Assy P vlue SWR-M SWR-J I Neck-shoulder '25IUdR 1.45 ± ± 0.27 <0.02 II Neck-shoulder '25IUdR <0.01 III Neck-shoulder '25IUdR 3.64 ± ± 0.96 <0.10 IV Neck-shoulder '25IUdR 6.26 ± ± 0.80 <0.05 V Neck-shoulder 51Cr 2.87 ± ± 1.96 <0.05 VI Neck-shoulder 51Cr 3.47 ± ± 1.08 <0.05 VII Ers 125IUdR 1.25 ± ± 0.23 <0.01 VIII Ers '25IUdR 2.43 ± ± 0.51 <0.01 IX Ers '25IUdR 2.70 ± ± 0.35 <0.01 See footnote b, Tble 3.

34 LALTOO AND KIND TABLE 7. Inhibition of contct sensitivity rection to oxzolone by the serum of mite-infested SWR-M mice Expt Assy Tretment' S/N rtio' P vlue I 125IUdR 4.70 ± 1.43 "'IUdR 1.90 ± 0.

5 34 LALTOO AND KIND TABLE 7. Inhibition of contct sensitivity rection to oxzolone by the serum of mite-infested SWR-M mice Expt Assy Tretment' S/N rtio' P vlue I 125IUdR 4.70 ± 1.43 "'IUdR 1.90 ± 0.20 <0.01O '25IUdR SWR-J serum 3.53 ± 0.65 <0.20c (NS)d II '25IUdR 2.39 ± 0.60 '25IUdR SWR-M serum 1.46 ± 0.23 <0.05' 125IUdR SWR-J serum 2.17 ± 0.16 <0.60c (NS)d "Oxzolone-sensitized SWR-J mice were injected intrperitonelly with 1.0 ml of SWR-M or SWR-J serum immeditely fter skin pinting with oxzolone. 'See footnote b, Tble 3. ' Level of significnce when compred with untreted SWR-J control mice. d NS, Not significnt. continul relese of histmine into the circultion by mite ntigens intercting with immunoglobulin E ntibodies present on mst cells of the skin (7). It is unlikely tht locl increse of mst cells is responsible for the observed decrese in cellulr influx. Mst cell numbers were incresed in the neck-suprscpulr res but not in the ers of mite-infested mice (Tble 2); however, decrese in cellulr influx occurred in both res (Tble 6). It hs recently been shown tht histmine cn modulte cellulr immune rections both in vitro nd in vivo (16-19; A. Schwrtz nd R. K. Gershon, Fed. Proc. 37:1353, 1978). A subpopultion of T lymphocytes hs been found in severl species (including mice) which bers histmine type-2 receptors (6, 10, 16). The stimultion of such T lymphocytes results in the suppression of (i) migrtion inhibition fctor, (ii) cytotoxic T lymphocytes, (iii) prolifertion induced by concnvlin A or phytohemgglutinin (17, 19, 25). A suppressor fctor hs recently been shown to be relesed from lymphocytes stimulted with histmine in vitro (19). We hve recently found tht removl of the mites from the skin of mice by treting the nimls with miticidl gent resulted in reversl of the suppression of contct sensitivity (H. Lltoo nd L. S. Kind, unpublished observtions). The histmine relesed by mite ntigen from sensitized mst cells my interct with lymphocytes which then suppress the influx of cells in contct sensitivity rections by relesing nonspecific suppressive fctor. The role of histmine in the suppression of contct sensitivity nd the nture of the nonspecific suppressor fctor in the serum of the miteinfested mice re currently under investigtion in our lbortory. It should lso be mentioned tht depression INFECT. IMMUN. of cell-medited immunity hs been reported in individuls with topic eczem nd elevted serum immunoglobulin E levels (8, 9). Findings in the mite-infested mouse my be vluble for n understnding of the etiology of this disese s well s for devising mens to control it. LITERATURE CITED 1. Asherson, G. L., nd W. Ptk Contct nd delyed hypersensitivity in the mouse. I. Active sensitiztion nd pssive trnsfer. Immunology 15: Brrig, Depression of cell-medited immunity following inocultion of Trichinell spirlis extrct in the mouse. Immunology 34: Blckwood, L. L., nd J. A. Molinri Effect of Trichinell spirlis infection on delyed hypersensitivity to heterologous ntigens. Int. Arch. Allergy Appl. Immunol. 57: Coulis, P. A., R. M. Lewert, nd F. W. Fitch Splenic suppressor cells nd cell medited cytotoxicity in murine schistosomisis. J. Immunol. 120: Gershon, R. K., P. W. Askense, nd M. D. Gershon Requirement for vsoctive mines for production of delyed-type hypersensitivity skin rections. J. Exp. Med. 142: Kedr, E., nd B. Bonvid Histmine receptorbering leukocytes (HRL). I. Detection of histmine receptor-bering cells by rosette formtion with histmine coted erythrocytes. J. Immunol. 113: Lltoo, H., nd L. S. Kind IgE ntibody response to mite ntigens in mite infested mice. Immunol. Commun. 8: Lobitz, W. C., Jr., J. F. Honeymn, nd N. W. Winkler Suppressed cell-medited immunity in two dults with topic dermtitis. Br. J. Dermtol. 86: McGedy, S. J., nd R. H. Buckley Depression of cell-medited immunity in topic eczem. J. Allergy Clin. Immunol. 56: Melmon, K. L, H. R. Bourne, J. Weinstein, nd M. Sel Receptors for histmine cn be detected on the surfce of selected leukocytes. Science 177: Miller, J. A. F. P., M. A. Vds, A. Whitelw, nd J. Gmble A rdioisotopic method to mesure delyed type hypersensitivity in the mouse. II. Cell trnsfer studies. Int. Arch. Allergy Appl. Immunol. 49: Otsuki, J. A., R. A. Grssick, D. Seymour, nd L. S. Kind The use of 'H serotonin relese from mst cells of the mouse s n ssy for meditor libertion. Immunol. Commun. 5: Ottesen, E. A., T. K. Smith, nd E. H. Kirkptrick Immune response to Trichinell spirlis in the rt. Int. Arch. Allergy Appl. Immunol. 49: Pelley, R. P., J. T. Ruffier, nd K. S. Wrren Suppressive effect of chronic helminth infection, schistosomisis mnsoni, on the in vitro responses of spleen nd lymph node cells to the T cell mitogens phytohemgglutinin nd concnvlin A. Infect. Immun. 13: Pelley, R. P., nd K. S. Wrren Immunoregultion in chronic infectious disese: schistosomisis s model. J. Invest. Dermtol. 71: Plut, M., nd I. J. Bermn Histmine receptors on humn nd mouse lymphocytes. J. Allergy Clin. Immunol. 61: Rocklin, R. E Modultion of cellulr immune response in vivo nd in vitro by histmine receptor-bering lymphocytes. J. Clin. Invest. 57: Rocklin, R. E., nd D. Greineder Histmine induced suppressor fctor (HSF): nture of stimulus

6 VOL. 26, 1979 nd effect. J. Allergy Clin. Immunol. 61: Rocklin, R. E., D. Greineder, B. H. Llttmn, nd K. L Melmon Modultion of cellulr immune function in vitro by histmine receptor-bering lymphocytes: mechnisms of ction. Cell. Immunol. 37: Sbbdini, E., A. Neri, nd A. H. Sehon Locliztion of non-immune rdioctively lbelled cells in the lesions of contct sensitivity in mice. J. Immunol. Methods 6: Selinger, C. B., nd R. D. Higginbothm Hypersensitivity responses to bee venom nd to mellitin. Int. Arch. Allergy Appl. 46: Scott, D. W., R. D. Schultz, nd E. Bicer Further studies on the therpeutic nd immunologic spects of generlized demodectic mnge in the dog. J. Am. Anim. Hosp. Assoc. 12: Svet-Moldvsky, G. J., G. S. Shghijn, I. Y. Chernykhovsky, D. M. Mkeidze, T. A. Litovehenko, N. N. Ozeretkovsky, nd L B. Kdghidze Inhibition of skin llogrft rejection in Trichinell infected mice. Trnsplnttion 9: Vds, M. A., J. F. A. P. Miller, J. Gmble, nd A. MITE-INFESTED MICE 35 Whitelw A rdioisotopic method to mesure delyed type hypersensitivity in the mouse. I. Studies in sensitized nd norml mice. Int. Arch. Allergy Appl. Immunol. 49: Wng, S. R., nd B. Zweimn Histmine suppression of humn lymphocyte responses to mitogens. Cell. Immunol. 36: Wrren, K. S., D. I. Grove, nd R. P. Peiley The Schistosom jponicum egg grnulom. II. Cellulr composition, grnulom size nd immunologic concomitnts. Am. J. Trop. Med. Hyg. 27: Weisbroth, S. H., S. Friedmn, nd S. Scher The prsitic ecology of the rodent mite, Myobi musculi. III. Lesions in certin host strins. Lb. Anim. Sci. 26: Weisbroth, S. H., M. B. Powell, L. Roth, nd S. Scher Immunopthology of nturlly occurring otodectic otocrisis in the domestic ct. J. Am. Vet. Med. Assoc. 165: Whiteley, H. J., nd D. H. Horton The effect of Myobi musculi on the epidermis nd hir regrowth cycle in the ging CBA mouse. J. Pthol. Bcteriol. 83: Downloded from on October 4, 2018 by guest

Modification by Suppressor Cells and Serum

Modification by Suppressor Cells and Serum Modifiction by Suppressor Cells nd Serum Fctors of the Cell-Medited Immune Response in Experimentl Pyelonephritis THOMS MILLER, LESLEY SCOTT, ELINE STEWRT, nd DEREK NORTH, Deprtment of Medicine, ucklnd