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Delayed Hypersensitivity (Colvin Et Al., Warfarin to Sensitized Guinea

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Delayed Hypersensitivity (Colvin Et Al., Warfarin to Sensitized Guinea Br. J. exp. Path. (1975) 56, 44 THE EFFECT OF ANCROD ON THE DELAYED HYPERSENSITIVITY RESPONSE IN RATS S. SILBERMAN AND H. C. KWN-AAN Fromn the Department ofPathology, Foster G. M.cGaw of Loyola University School of Medicine, Mfaywood, Illinois 60153, and the Department of Medicine, Veterans Administration Research Hospital and Northwestern University-M3lcCaw l,Medical Center, Chicago, Illinois Received for publication 10 September 1974 Summary.-Delayed hypersensitivity was induced in rats by means of sheep ery- throcytes and bovine serum albumin-lipid conjugate. Administration of heparin to rats sensitized to either antigen resulted in diminution of the delayed hyper- sensitivity reaction. Administration of ancrod, however, failed to inhibit the delayed cellular reaction to either antigen. Granuloma formation remained unaffected when rats were injected with either heparin or ancrod. The lack of ancrod effect, in contrast to heparin effect, on delayed hypersensitivity is discussed. SEVERAL lines of evidence now suggest the delayed hypersensitivity reaction. that fibrin deposition plays a vital part in The present study seeks to evaluate the various types of inflammatory processes, effects of ancrod and heparin on the including the tissue reaction mediated by cellular reaction of the rat purposely delayed hypersensitivity (Colvin et al., immunized in a manner favouring the 1973). Administration of heparin or development of delayed hypersensitivity warfarin to sensitized guinea-pigs re- upon skin testing, with sheep red blood sulted in diminution or prevention of the cells (Axelrad, 1968) and bovine serum delayed hypersensitivity reaction (Cohen albumin-lipid conjugate (Coon and Hun- et al., 1967). Ancrod, the purified fraction ter, 1973) used as immunogens. prepared from the venom of the Malayan pit viper, has shown effective anticoagulant properties (Bell, Pitney and Goodwin, MATERIALS AND METHODS 1968). Other studies, however, have Sprague-Dawley female rats weighing 250 provided evidence that ancrod, through 300 g were used. Two in vivo models of the its defibrinating action, interferes with the delayed cellular response were utilized in this normal process of wound healing in study: sensitization to a particulate antigen, rabbits (Holt et al., 1970). Silberman and sheep red blood cells (SRBC) and to a soluble antigen, boxine serum albumin-lipid conjugate Kwaan (1971) have likewise shown that (D-BSA). ancrod causes delayed formation of Sheep red blood cell sensitization (SRBC).- granulating tissue in implanted clots in The preparation of SRBC and the sensitization rats. Studies on the cellular response of programme were carried out as described by Axelrad (1968). Animals were subdivided into the delayed hypersensitivity reaction have :3 groups: Groups A, B, and C. shown that the inflammatory cell response Group A consisted of 10 rats which served as is no different in immune inflammations control animals. The group w%vas subdivided from that in nonspecific inflammatory equally into Groups Al and A2. Group Al rats reactions (Spector, 1967). These observa- were sensitized with a solution of equal volumes of Freund's Complete Adjuvant (FCA) and tions suggested studies to determine saline, then skin tested with SRBC. Group A2 whether hypofibrinogenaemia induced by rats received no prior sensitization but were skin ancrod will influence the development of tested with SRBC as described below. DELAYED HYPERSENSITIVITY RESPONSE IN RATS 45S Group B was subdivided into 2 groups, B1 and Bauer, Flushing, N.Y.) according to the and B2, of 15 rats each. Both groups were method of Coon and Hunter (1973). The molar sensitized and challenged with SRBC. In ratio of the anhydride to the BSA solution was addition, Group B2 rats were injected with 500: 1. Animals were divided into Groups D, ancrod (kindly supplied by Abbott Laboratories, E and F. North Chicago). Ancrod was injected through The control Group D, containing 10 rats, the tail vein, 57 u/kg body weight every 12 h was subdivided equally into Groups D1 and D2. beginning 24 h before challenge and throughout Group D 1 rats were sensitized with equal the skin testing period. Adequate defibrination volumes of FCA and saline, then skin tested with was ensured by measuring a citrated sample of D-BSA. D2 animals were skin tested without plasma for fibrinogen at the termination of the prior sensitization. Group E, containing a total experiment by means of a thrombin clotting of 30 animals, was subdivided into 2 groups of assay. All animals were sensitized intra- 15 rats each-E 1 and E2. Both groups were dermally with a 5% saline suspension of fresh sensitized with 50 mg of conjugate in 0.1 ml SRBC mixed with an equal volume of FCA. A of FCA injected intradermally into the left rear total of 0 5 ml of emulsion was injected over 3 paw and skin tested with BSA. Group E2 rats sites along the nipple line. in addition received ancrod, in similar manner Group C consisted of 10 rats sensitized and to Group B2 animals, 24 h before and during the challenged with SRBC, in whom heparin was challenge period. Group F consisted of 10 rats substituted for ancrod as anticoagulant. Hep- sensitized with D-BSA in FCA and challenged arin (obtained from Upjohn Co., Kalamazoo, with BSA. This group received heparin in dose Michigan (1000 u/ml)) was administered intra- and manner similar to Group C rats. peritoneally 1000 u/kg body weight twice daily Skin testing was carried out on all groups 24 h before skin testing with SRBC and through- 12 days following sensitization with a solution out the experimental procedure. Adequate of 50 ,ug BSA in 0 1 ml saline intradermally anticoagulation was ensured by measuring the over the pre-shaven flank. The skin reactions whole blood clotting time. were examined 24 h later for erythema and For evaluation of skin test sensitivity to induration and the skin diameters measured in sheep erythrocytes, increased paw size was mm. At this time maximal swelling and measured following injection of SRBC. Ani- erythema were observed, whereas at 48 and 72 h mals were injected intradermally on the dorsal after injection of antigen, the swelling and ery- surface of the left rear hind paw with 0.1 ml of a thema were decreased. The animals were bled 7-5% suspension of SRBC in saline on the ninth for determination of fibrinogen, and serum day following sensitization. Saline in equal samples from 10 animals were tested for the volume was injected in the other hind paw. presence of antibodies to BSA by agar immuno- Twenty-one h later the animals were anaes- diffusion. The animals were sacrificed and sec- thesized with Nembutal (pentobarbitone sodi- tions taken from sensitization and skin test um) intraperitoneally and the skin test reaction sites for histological examination. to SRBC was evaluated. The cellular response Statistical evaluation.-The results obtained was measured by weighing each rear hind paw in each sensitized group were compared with into a pre-weighed beaker containing mercury. those in the respective control group. The The difference in weight between the challenged results of experiments with heparin and ancrod left hind paw and the saline injected paw was also were compared with those of the corres- expressed as the percent increase of paw vol- ponding untreated sensitized group. The sig- ume subsequent to challenge with the antigen. nificance of the differences was established by To test for significant difference in weights Student's " t " test. between right and left hind paws of untreated animals, 20 random rats were examined in similar fashion. The animals were anaesthe- sized and the weights of right and left rear hind RESULTS paws were measured and the percent difference computed. Serum samples from 10 sensitized Plasma fibrinogen levels were main- rats were obtained 4 days after the sensitizing injection and at the end of the experiment; tained below 50 mg/100 ml in all ancrod SRBC agglutinin titres were determined on injected rats. Control values in normal these samples. All animals were subsequently animals ranged from 150 to 350 mg/100 sacrificed and sections from both rear hind paws ml. The heparinized animals exhibited as well as from the initial site of sensitization clotting times greater than 30 min when were taken for histological examination. Bovine serum albumin (BSA)-lipid sensitiza- measured 3 h after the last heparin tion (D-BSA).-BSA, 25 mg/ml was conjugated injection. Values averaged 5 min in with a lipid, dodecanoic anhydride (Pfaltz normal animals. 46 S. SILBERMAN AND H. C. KWAAN TABLE I. Percent Weight Gain acnd Standard Deviations Obtained 21 hfollowing Challenge with Sheep Erythrocytes in Sensitized Untreated Rats (Group B1), Sensitized Ancrod Treated Rats (Group B2), Sensitized Hepacrin Treated Rats (Group C) and Control Rats (Groups A 1 and A 2) l\lean i'espoiise Treatment ( %) an({ No. of AnCro(t Hepari' stan(lar(l Grouips ainimals stu(Iied Sen.sitization Challenge Arlero(l Hepai ill deviatioll A1 CFA + saline SRBC 28- 1 7 A2 SRBC 3 I19 B, 1. CFA + SRBC SRBC 22* X 6 B2 15 CFA + SRBC SRBC 14 8-t ± 7 2 7 C 10 CFA + SR13C SRBC 5-7+ - * Differs signiificantly from control Group A (P < 0 1()). t Differs significantly from control Group A (P < (0) )01). + Does not differ significantly from control Group A (P > () 1). SRBC sensitization the response in Group B1 rats, the increase Random untreated animals showed in paw swelling was not markedly signi- slight variations in foot pad size between ficant at the 0 05 level. the right and left hind paws, dependant In Group C animals, the left hind paws on the animal size. The average percentile showed bluish discoloration due to sub- difference in weight computed in 20 cutaneous bleeding in 4 rats, otherwise normal rats by subtracting the weights of minimal swelling was observed.
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