Allergies of the dental pulp

endodontics Editor: MILTON

SISKIN, D.D.S.

College of Dentistry The University of Tennessee 847 Monroe Avenue Memphis, Tennessee 38 I63

Allergies of the dental pulp V. W. Adamkiewicz,* D. D. PekoviC,** and C. MascrGs,*** Montreal, Quebec, Canada UNIVERSITY

OF MONTREAL

A review of publications relating to the allergies of the dental pulp is presented.The pulp-especially when inflamed-contains antigens, lymphocytes, plasmocytes, IgG, IgM, IgA, and IgE antibodies, mastcells, histamine, and possibly C3. However, no antibody-mediatedallergy (hypersensitivity) of the pulp has yet been demonstrated.On the other hand, two types of cell-mediated allergy-the graft-rejection reaction and contact hypersensitivity-have been reported, as well as autoimmunity.

T

he immunology of the oral cavity, immunodentistry, comprises essentially in the following three types of body compartments:

reactions that occur

I. The sheltered compartment. It has no direct contact with the outside environment and is composed mainly of the dental pulp. The present review is confined to allergies occurring only in this compartment. 2. The semisheltered compartment. It displays a limited contact with the outside environment. An example is the gingival sulcus. 3. The unsheltered compartment. It opens directly to the outside environment and includes the oral cavity itself.

Both the nonspecific and specific immunologic reactions taking place in these compartments result from the activity of cellular as well as molecular factors. The nonspecific cellular and molecular factors kill or arrest rather indiscriminately the growth of most of the harmful microorganisms. The main nonspecific cellular factor is phagocytosis, while the nonspecific molecular factors are numerous and comprise lytic substances, such as interferon, complement, properdin, etc. On the other hand, the cells taking part in the specific immune reactions are lympho*Professor of Immunology, Faculty of Medicine. **Graduate Student, Faculty of Medicine. ***Associate Professorof Stomatology, Faculty of Dental Medicine 0030-4220/78/120843+I

I$Ol.lO/O 0

1978 The C. V. Mosby Co.

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cytes, especially the T lymphocytes, while the molecules are the various types of antibodies produced by the B lymphocytes. However, in addition to acting selectively against a given type of microorganism, the specific immunologic reactions may also lead to allergy, and even to immune tolerance. The specific immunologic reactions in the three types of compartments of the oral cavity are invariably triggered by antigens, or by haptens, of five different origins. On very rare occasions, the antigens arise from the oral tissues of the individual. What follows in such a case is an oral autoimmunity or autoallergy. Only one example is reported in the present review. Second, the antigens may be of a systemic origin, irrespective of their ultimate source. In that case, they are simply brought into one of the three compartments of the oral cavity from the other parts of the body. Third, the antigens may come from the oral flora, especially the dental plaque. Fourth, the antigens may be of an iatrogenic origin and be released from the restorative materials used by the dentist. Fifth, and finally, the exogenic antigens are those brought in with the air, beverages, foods, and pharmaceuticals that enter the oral cavity and by contact. As for the haptens, they are mostly systemic, iatrogenic, or exogenic. The present review is based on the following classification: 1. Antibody-mediated allergy (hypersensitivity). Type I : atopic, anaphylactic I6 Type II : cytotoxic’” Type III: Arthus and antigen-antibody complexes’” 2. Cell-mediated allergy (hypersensitivity). Tuberculin-type: against antigens Contact-type: against haptens Host-versus-graft (HVG): graft rejection Graft-versus-host (GVH): an attack on the host by the immunocompetent cells of the graft 3. Antibody- and/or cell-mediated allergy (hypersensitivity). Autoimmunity: autoallergy 4. Tolerance. A condition in which responsive cell clones have been eliminated or inactivated by prior contact with antigen, with the result that no immune response occurs on the administration of antiger?” It may be added that the Type I reactions are produced by pharmacologically active substances (histamine, serotonin, kinins, prostaglandins, etc.) released from cells (mast cells, basophils, platelets) following the combination of antigen with specific antibody. Type II reactions involve the combination of antigenic determinants on cell membranes with the specific antibody. They are considered to be cytotoxic because they frequently involve complement fixation and cell damage. Type III reactions are secondary to the localization of antigen-antibody complexes, with inflammation being the main feature.R3 Theoretical frameworks for the study of aIlergy in oral diseases in general have been proposed in the past.i* 42, 72 However, as recently as 1975, the authors of standard textbooks have not considered hypersensitivity to be a possible cause of pulpal lesions. Two general conclusions may be drawn from the present review:

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1. No antibody-mediated allergy has been observed as yet in the dental pulp. 2. Two types of cell-mediated allergy-the host-versus-graft reaction and contact hypersensitivity-have been reported, as well as autoimmunity. ANTIBODY-MEDIATED

ALLERGY (HYPERSENSITIVITY)

Although an antibody-mediated allergy is yet to be demonstrated in the dental pulp, such a demonstration may not be too far off, because the pulp contains the necessary antigens, antibodies, and pharmacologically active substances. Thus, as would be expected, the pulp itself is antigenic. The allogeneic grafts of teeth containing the pulp stimulate the local lymphatic nodes of the host animal.2s’ 45Rat pulp is antigenic in rabbits61 and rabbit pulp is antigenic in other rabbits.62, 86 However, in rats following orthotopic grafting of allogeneic teeth containing the pulp, the antibody production was found to be somewhat “capricious.“35 Indeed, it was thought that the antigenicity of the pulp was lower than that of other tissues.64 The cytologic changes in the regional lymph nodes induced by allogeneic pulp grafted to rabbits occurred later than changes following grafts of other allogeneic tissues.*‘j It was suggested that, in rats, tooth buds contain fewer histocompatibility antigens than other tissues.*’ The view that the pulp and tooth buds are less antigenic than the other tissues subsequently has been challenged. Allogeneic grafts of intact rabbit teeth were shown to be as antigenic as skin grafts.27 H-2 histocompatibility antigens have been identified on the mesenchymal and epithelial surfaces of embryonic teeth in mice.74 It is mainly these types of antigens that are being recognized by the host’s immune apparatus upon transplantation and induce the cytologic changes in the regional lymph nodes. Furthermore, allogeneic pulp grafts induce an accelerated rejection of second-set skin grafts in rabbits.38, 86Orthotopic allografts of teeth containing the pulp are as effective as skin allografts for the induction of second-set skin graft rejection in rats that are incompatible at the major histocompatibility locus. Not surprisingly, the immunogenicity of such teeth decreases upon making the pulpal antigens unavailable by sealing the pulpal chamber before transplantation.3” It has been suggested that pulpal components become antigenic upon degeneration,6J and that changes in chronically inflamed pulps lead to an autosensitization to the pulpal autoantigens. 2g,4oThe injection of a suspension of allogeneic pulp in complete Freund’s adjuvant induces autoimmune pulpal lesions in rabbits.61, 62 Some pulpal antigens appear to cross-react with antigens of other tissues. Thus, rabbit antiserum against allogeneic pulp cross-reacts not only with extracts of allogeneic vessels but also with extracts of self vessels. 61 Pulpal grafts sensitize the animal to subsequent skin grafts.38, 86 The pulp, in addition to being antigenic, also contains antigens of systemic origin, especially those that are part of microorganisms. Stanley7J reported the presence of specific microorganisms in the pulps of patients with tuberculosis, leprosis, actinomycetosis, and aspergillosis. Hyperemia and hemorrhages were found in the pulps of mice injected with virus systemically or born from virus-infected mothers.3s Circulating substances find their way into the pulp easily. For example, radioactive p2 injected systemically was found in young teeth of rats grafted to guinea pigs.82 The pulp may also contain antigens from the oral flora. An exposed pulp becomes

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readily infected with oral bacteria in rats. 6oAfter examining 612 human pulps, MejareJo found 92 containing species of streptococcus. Following experimentation with monkeys treated with human dental plaques, it was suggested that some soluble factors from the plaques could induce inflammatory changes in the pul~.~ Out of 15 teeth that displayed a hypersensation to pain in the region of the neck of the tooth, 14 also showed an inflammatory reaction in the pulp. 71A correlation between periodontal diseases on the one hand and inflammation, degeneration, and necrosis of the pulp on the other was observed. It was suggested that the periodontal diseases influence the pulp via the lateral accessory canals6 There is little doubt that the oral flora may establish a direct contact with the pulp and invade it, particularly through deep caries. The introduction of microorganisms and antigens into the root canal indeed leads to systemic immune responses, such as skin reactions and antibody production. 5, 36,~2 7oIn addition, evidence has accumulated in favor of the possibility that a direct contact may be established between microorganisms and the pulp through restorative cavities. Brannstrijm and Vojinovi?” stated that “no permanent filling material adheres completely to dental hard tissues. Most materials . . contract on setting, which accounts for space of variable size between the filling and the cavity walls.” The size of this space is of the order of 2 to 20 pm., while the average size of a bacterium is of the order of 1 Wm. Therefore, the space may become quickly and completely filled with bacteria.“-I4 This growth of the microorganisms on the walls of the cavity “is due in part to an invasion of the bacteria from the oral cavity. In part it is due to the continued growth of bacteria already present in the cavity at the time the filling was inserted.“13 These bacteria often come from the dentinal debris produced during the preparation of the cavity”3 and remain viable under the fillings. a0In a series of in vitro experiments, Olgart and associateP demonstrated that bacteria infiltrate and penetrate dentinal tubules over a distance of 0.1 to 2.0 mm. On the other hand, it has been known for some time that, following various operations on the dentin, the odontoblastic nuclei move from the pulp into the dentinal tubules. lo Thus, the distance separating bacteria and pulp in a restorative cavity is further diminished. “Toxins” from the invading bacteria were suggested as the main cause of pulpal irritation in teeth restored with composite resins and zinc phosphate. ‘a, I4 The extracellular fluid present in the dentinal canals may indeed provide a medium for the diffusion of antigenic or haptenic substances into the pulp. Finally, the pulp may contain haptens of iatrogenic origin. The allergenic property of several materials employed in clinical odontology was demonstrated by standard tests in guinea pigs. 14Components of silicate cement “are capable of penetrating a considerable thickness of dentine” if the cavity is not lined. 7x As for the lining materials themselves, their penetrating and haptenic effects are little known. The normal intact human dentin and cementum are permeable to water and solutes of low molecular weight which cross the tooth in about 24 hours, as has been demonstrated in vitro.“” Such acute in vitro experiments, however, may not necessarily apply to the living tooth, in which several defense mechanisms against the intrusion of extrinsic materials may become operative over longer periods of time.‘” Concerning the presence of antibody, a distinction may be made between normal and inflamed p~lps.~~ As would be expected, normal pulps in general contain little, if any, antibody-producing cells and antibody molecules. However, as the intensity of the pulpal inflammation increases, so do the number of cells and the amounts of antibody.

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Apparently, some potentially antibody-producing cells, such as lymphocytes and possibly plasmocytes, have been seen occasionally in normal pulp~,~’ but in inflamed pulps their numbers become considerable. 67*~3 87It should not be surprising that circulating antibodies find their way into the normal pulp and that antibody-like substances have been noticed in the vascular and connective tissues of normal human pulp through use of fluorescent anti-IgG serums.@ The presence of (or, CQ,/3, and y globulins and of antibody has been demonstrated in inflamed pulps of experimental animalsz9 30,31and man.66 The antibody produced by the cells in inflamed human pulps has been shown to be mainly IgG, some IgA, IgM, and IgE.‘jj, 66 In addition, the pulp appears to be a potential site for the Type I allergies, such as atopies and anaphylaxis. Thus, the presence of mastocytes in the pulp has been reported. 23, 83, 78 However, here again a distinction may be made between normal and inflamed pulps. ” Normal human pulps contain few,‘* 23 if any,“: mastocytes, whereas these cells are numerous in inflamed p~lps.~” A fourfold increase of pulpal histamine was reported following a thermal injury. lg The presence in the pulp of IgE, which is the antibody usually associated with Type I allergies, has also been reported.66* 67 There is some indirect evidence of a potential Type II allergy in the pulp. Pulpal cells carry antigens, as mentioned in the section dealing with pulpal antigenicity. Also, as already mentioned, antibody-producing cells and antibody molecules, especially IgG and IgM, were found mainly in infiamed pulps. In addition, C3, probably of systemic origin, has been observed occasionally in inflamed pulps using fluorescein-labeled antisera.66, 67 Thus, the main elements involved in an immune cytotoxic reaction are usually present in the pulp. The Type III allergy results from a localization of antigen-antibody complexes. The following, taken from Pulver and colleagues,67 is apparently the only reference regarding the possible presence of such complexes in the pulp: “persistent (fluorescein-labeled) IgG staining of connective tissues and vessels in inflamed pulps . . . may indicate a level of IgG binding to these tissues . . . or the presence of immune complexes.” CELL-MEDIATED ALLERGY (HYPERSENSITIVITY)

1

An allergy is cell mediated when it results from a reaction between sensitized lymphocytes and a specific antigen. The sensitized cells are T lymphocytes. Antibody and complement are not involved.83 Apparently some lymphocytes occur occasionally in normal human p~lps.~” Their number increases with the intensity of inflammation. 67*85 Although the T lymphocytes themselves have yet to be identified in the pulp, their presence was demonstrated indirectly by Pekovic and co-workers. ‘* The following in vivo macrophage migration inhibition test was devised for this purpose (see also “Autoimmunity.“): Rabbits were sensitized with allogeneic pulp in complete Freund’s adjuvant. A suspension of allogeneic macrophages was then sealed atop the pulp of the mandibular incisors. The incisors were removed the following day, sectioned, and examined histologically. The migration of the allogeneic macrophages along the pulp toward the apex was then evaluated. This migration was found to be greatly inhibited or completely stopped in the sensitized rabbits, as compared to the migration in the pulp of unsensitized control rabbits. An analogous specific inhibition of macrophage migration in vitro has often been demonstrated previously. The inhibition is thought to demonstrate the presence of T lymphocytes, because

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sensitized T lymphocytes are supposed to release the macrophage migration inhibition factor upon reaction with specific antigen.69 With reference to the tuberculin or infection type of allergy in the pulp, the following facts may be mentioned. Oral bacteria3’ and actinomyces”” have been shown to produce a tuberculin-like allergy in the skin of patients. The presence of specific microorganisms has been reported in the pulp of patients with tuberculosis, leprosis, actinomycetosis, and aspergillosis.7” Despite this, however, no evidence exists to date of a tuberculin type of allergy in the dental pulp. Contact

type of cell-mediated

allergy

(hypersensitivity)

Contact-type allergies are produced by haptens mainly of iatrogenic, or experimental, origin. They are readily observed in the oral cavity, as elsewhere in the body, and have been among the first and the most frequently reported.2” Cases of contact allergies in various parts of the body, other than the pulp, to amalgam fillings are well known. 22, ~3 76 In addition, contact allergies to several other dental materials have been demonstrated by means of skin tests in guinea pigs.“4 The production of an experimental contact allergy in the pulp itself has been reported from our laboratory by Mascres and associates.46-4g Rabbits were sensitized during a 16day period with five intradermal injections of the hapten l-chloro-2,4-dinitrobenzene. The pulp of four incisors was then challenged with 1 pg of the hapten dissolved in 0.001 ml. of olive oil. A control group of rabbits which were not sensitized was challenged in the same manner. The incisors were removed the following day, sectioned, and examined histologically. It was found that the pulps of the sensitized rabbits displayed a considerable serous inflammation and accumulation of inflammatory cells. The extent of the inflammation and the number of cells was about two and one half times greater than in the control rabbits. The cells included numerous eosinophils. Host-versus-graft

(HVG) type of cell-mediated

allergy

(hypersensitivity)

The host-versus-graft reaction, or graft rejection, is the oldest, most frequently reported, and, to-date, the most studied type of tooth and pulp allergy. Apparently, it was Ambroise Pare (c. 1510-1590), a celebrated French surgeon, who was the first to report an unsuccessful tooth transplantation.i7 In England, John Hunter ( 172% 1793) also tried it .33In the course of the last century, attempts at tooth transplantation became frequent.ix, 24,41*S3*63Not much may be said about the state of the pulp and its response to the transplantation during these early experiments. In the second half of the twentieth century, the transplantation of teeth has produced a vast and specialized literature. Only a brief reference to it may be made here, with special emphasis on those rather sparingly reported aspects which concern the pulp itself. At the same time, and whenever possible, it will also be necessary to distinguish the changes in the pulp caused by the cell-mediated allergy itself from those due to other causes. The pulp remains viable for a time after removal from the host.“Y An elaborate electron microscopic study disclosed no major alterations in the pulps of dogs 30 minutes after detachment from the blood circulation. x Today, various methods exist for keeping teeth, pulp, and tooth germs alive before implantation. Orthotopic and heterotopic autotransplantation of teeth are the only operations where

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no graft rejection may be expected, since the antigenic composition of graft and host remains the same. In such cases there should occur: No postoperative reactions, a complete gingival consolidation, no periapical reaction, a reconstitution of an almost normal ligamentous area, and a re-established vitality demonstrated by thermal and electrical tests.17

In all other transplantations, the tooth and the pulp bring new antigens. A hostversus-graft reaction appears to be inevitable, as was foreseen by Delquel*‘* ” at the beginning of this century. Teeth transplanted at various stages of their development have been rejected in experimental animals.3* “3 34, 45 The pulp of allografts in mice has undergone an acute inflammation and degeneration.37j 38, j1 A massive infiltration by lymphocytes was reported in orthotopic allografts of teeth in Syrian hamsters sensitized to skin6* Similar cellular changes have been reported in allografts of tooth buds in rats.34, 81The second-set allografts, of lo-day-old teeth, were rapidly and heavily infiltrated by mononuclear leukocytes in mice.4 The germs, buds, and young teeth hold a special place in the literature on transplantation. It is believed that “for purposes of transplantation a dental germ in an early stage of development is better than one that has fully matured.“i7 Should there be any ground for such a view, the reasons would less likely be immunologic than anatomic. An incompletely differentiated periodontal and pulpal tissue is more resistant than a mature tooth to the ischemia that accompanies transplantation. An incompletely developed apical region, an open aperture, and a wide root canal all facilitate the anastomosis of nerves and vessels” and result in a temporary “take” of the graft. (See also the section on “Tolerance.“) As for the occurrence of the graft-versus-host reaction (GVH) in the dental pulp, there is as yet no evidence in the pertinent literature. One has to bear in mind, however, that the immunocompetent cells are sparse in normal pulp, if present at all. ANTIBODY- AND/OR CELL-MEDIATED ALLERGY (HYPERSENSITIVITY) Autoimmunity (autoallergy)

An autoimmunity reaction takes place whenever there is immunity to self-antigens leading to self-injury. This description implies no etiologic mechanisms.7g An experimental autoimmune hypersensitivity reaction in the pulp was reported recently from our laboratory. 60-62Rabbits were sensitized with three injections of allogeneic pulp in complete Freund’s adjuvant. A control group of rabbits received the adjuvant alone, without the pulp. On the twenty-second day, a macrophage migration inhibition test was carried out in vivo. For this, freshly harvested allogeneic macrophages from the peritoneal exudate of a donor rabbit were sealed atop the pulp of the mandibular incisors in both groups of rabbits. (See also the section on “Delayed pulpal hypersensitivity. “) The following day the rabbits were killed and their teeth were examined histologically. A search was made in the pulp of these teeth for the presence of autoimmune lesions and for the inhibition of the migration of the allogeneic macrophages. In 24 teeth examined from the group of sensitized rabbits, 33 lesions were found. No lesions were found in 23 teeth examined from the control group.

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In addition, the migration of macrophages was greatly inhibited in the group of sensitized rabbits. The coronal half of the pulp of the incisors in these rabbits contained one sixth the number of migrating macrophages in the control group. No migrating macrophages were found at all in the apical half of the pulp of the experimental rabbits. In the control group, on the other hand, the macrophages had migrated in great numbers along the entire length of the pulp of the incisor teeth. The autoimmune lesions of the pulp were produced in these experiments by means of allosensitization, using an allogeneic pulp. In another experiment, xenosensitization was tried”l by injecting rabbits with rat pulp in complete Freund’s adjuvant.“’ However, no lesions were obtained by this procedure. TOLERANCE

A tolerance is nonspecific when the animal tolerates all the antigens by responding to none. This results from a general failure of the immune apparatus and usually is incompatible with the survival of the individual. On the other hand, there is specific immune tolerance when the individual fails to respond to one or to a few antigens only, while responding to all others. With respect to the dental pulp, it has been suggested that teeth and pulp are less antigenic than other tissues and are thus specifically tolerated. The allogeneic teeth and tooth germsJ4, 64and even xenogeneic tooth germs9 were supposed to be tolerated by the host in animal experiments. (See also the section, “Host-versus-graft reaction.“) Such opinions have since been mostly refuted.Z3,a434.i However, the demonstration of specific tolerance toward the antigens of the pulp must always remain a possibility. One suggested mechanism is the masking of pulpal antigens by some “intercellular substance.“R6 REFERENCES I. Anneroth, G., and Br%nnstrom, M.: Autofluorescent Granular Cells and Mast Cells in the Human Gingiva and Dental Pulp, Odontol. Revy. 15: 10-14, 1964. 7-. Aono, M., Yoshida, M., Munemoto, K., Okada, H., and Yokomizo, I.: J. Osaka Univ. Dent. Sot. 9: 53-62, 1964. Cited in Honjo, H., Tsubakimoto, K., Utsumi, N., and Tsutsui, M.: Localization of Plasma Proteins in the Human Dental Pulp, J. Dent. Res. 99: 888, 1970. 3. Apfel, H.: Transplantation of the Unerupted Third Molar Tooth, ORAL SURG. 9: 96-98, 1956. 4. Atkinson, M. E.: A Histological Study of Tooth Allografts Transplanted to Untreated and Immunologically Prepared Mice, J. Oral Pathol. 4: 167-179, 1975. 5. Barnes, G. W., and Langeland, K.: Antibody Formation in Primates Following introduction of Antigens Into the Root Canal, J. Dent. Res. 45: I1 I I-1 114, 1966. 6. Bender, 1. B., and Seltzer, S.: The Effect of Periodontal Disease on the Pulp, ORAL SURG. 33: 458-474, 1972. 7. Bergenholtz, G., and Lindhe, J.: Effect of Soluble Plaque Factors on Inflammatory Reactions in the Dental Pulp, Stand. J. Dent. Res. 83: 153- 158, 1975. 8. Bickley, H. C : A Concept of Allergy With Reference to Oral Disease, J. Periodontal. 41: 302-3 12, 1970. 9. Bjedl, W., and Weizenberg, J.: Uber die Transplantation von Zahnkeimen, Beweis fur die Echtheit heteroplastischer Zahnkeimtransplantationen. IV. Mitteilung, Acta Anat. Base1 30: 44-66, 1957. IO. Brannstriim, M.: Dental and Pulpal Response. Vi. Some Experiments With Heat and Pressure Illustrating the Movement of Odontoblasts Into the Dentinal Tubules, ORAL SURG. 15: 203-212, 1962. II. Brannstrom, M., and Nyborg, H.: The Presence of Bacteria in Cavities Filled With Silicate Cement and Composite Resin Materials, Sven. Tandlak. Tidskr. 64: 149- 155, 1971. 12. Brlnnstriim, M., and Nyborg, H.: Pulpal Reaction to Composite Resin Restorations, J. Prosthet. Dent. 27: 181-189, 1972. 13. Brannstrdm, M., and Nyborg, H.: Cavity Treatment With a Microbicidal Fluoride Solution: Growth of Bacteria and Effect on the Pulp, J. Prosthet. Dent. 30: 303-310, 1973.

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14. BrinnstrGm, M., and Nyborg, H.: Bacteria1 Growth and Pulpal Changes Under Inlays Cemented With Zinc Phosphate Cement and Epoxylite CBA 9080, J. Prosthet. Dent. 31: 556-565, 1974. 15. Brinnstriim, M., and VojinoviC, 0.: Response of the Dental Pulp to Invasion of Bacteria Around Three Filling Materials, J. Dent. Child 43: 83-89, 1976. 16. Coombs, R. R. A., and Gel], P. G. H.: Classification of Allergic Reactions Responsible for Clinical Hypersensitivity and Disease. In Gel], P. G. H., Coombs, R. R. A., and Lachmann, P. J. (editors): Clinical Aspects of Immunology, Oxford, 1975, Blackwell Scientific Publications, p. 761. 17. Dahan, J.: Dental Transplants: Hopes and Realities, Image (Medical Illustrated Roche, Basle, Switzerland) 46: 2-1 I, 1972. 18. David, T.: Etude sur la Greffe Dentaire, Paris, 1877, J. B. Bailliere et Fils. 19. Del Balsa, A. M., Nishimura, R. S., and Setterstrom, I. A.: The Effect of Thermal and Electrical Injury on Pulpal Histamine Levels, ORAL SURG. 41: 110-I 13, 1976. 20. Delquel, P.-A.: Notes sur la Greffe Dentaire, Gaz. Hebd. SC. Med. Bordeaux 31: 176-180, 1910. 21. Delquel, P.-A.: Cas de Greffe Autoplastique (Optration de Magitot), Gaz. Hbd. SC. Med. Bordeaux 35: 65, 1914. 22 Djerassi, E., and Berova, N.: The Possibilities of AIlergic Reactions From Silver Amalgam Restorations, Int. Dent. J. 19: 481-488, 1969. 23. Dockrill, T. E.: Tissue Mast Cells in the Oral Cavity, Aust. Dent. J. 6: 210-214, 1961. 24. Fletcher, M. H.: Some Notes on Experimental Implantation of Teeth, Ohio J. Dent. Sci. 11: I- 15, 1891. 25. Frykholm, K. 0.: On Mercury From Dental Amalgam; Its Toxic and Allergic Effects and Some Comments on Occupational Hygiene, Acta Odontol. Stand. 15: 8-20, 1957. 26 Fudenberg, H. H., Stites, D. P., Caldwell, J. L., and Wells, J. F. (editors): Basic and Clinical Immunology, Los Altos, Calif., 1976, Lange Medical Publications, p. 623. 21 Goldstein, B. H., Tissot, R. E., Laskin, D. M., and Cohen, C.: Histocompatibility and Tooth Transplantation in the Rabbit, ORAL SURG. 39: 929-933, 1975. 28 Haley, E. W., and Costich, E. R.: Lymph Node Response to Allografts of Teeth, J. Dent. Res. 46: 628, 1967. 29 Hattyasy, D.: Preliminare untersuchungen beziiglich der chronischen pulpitis und deren immunobiologische aspekte, Osterr. Z. Stomatol. 70: 202-208, 1973. 30 Henocq, E., Sebald, M., Bataille, R., Lehmans, J., and Meaume, J.: Hypersensibilitt aux microbes anaerobies d’origine bucco-dentaire, Rev. Stomatol. (Paris) 73: 21-30, 1972. 31 Honjo, J., Tsubakimoto, K., and Sumitani, M.: Homologous Plasma Proteins in the Human Dental Pulp, J. Ohio Dent. Univ. 2: 147-254, 1968. 13 Honjo, J., Tsubakimoto, K., Ustumi, N., and Tsutsui, M.: Localization of Plasma Proteins in the Human Dental Pulp, J. Dent. Res. 99: 888, 1970. 33. Hunter, J.: The Natural History of the Human Teeth: Explaining their Structure, Use, Formation, Growth and Diseases, ed. 2, London, 1771, J. Johnson, p. 136. 34. Ivanyi, D.: Immunologic Studies on Tooth Germ Transplantation, Transplantation 3: 572-576, 1965. 35. Kardos, T. B., and Heslop, B. F.: The Immunogenicity of Tooth Allografts in Rats, Transplantation 20: 381-384, 1975. 36. Kennedy, D. R., Hamilton, T. R., and Sylverton, J. T.: Effects on Monkeys of Introduction of Haemolytic Streptococci Into Root Canals, J. Dent. 36: 496-506, 1957. 37. Klein, J.: Tooth Transplantation in the Mouse. III. The Role of Minor (non H-2) Histocompatibility Loci in Tooth Germ Transplantation, Transplantation 12: 500-508, 1971. 38. Klein, J., and Secosky, W. R.: Tooth Transplantation in the Mouse. II. The Role of the Histocompatibility-2 (H-2) System in Tooth Germ Transplantation, ORAL SURG. 32: 513-521, 1971. 39. Kreshover, S. J., and Hancock. J. A.: The Effect of Lymphocytic choriomeningitis on Pregnancy and Dental Tissues in Mice, J. Dent. Res. 35: 467-478, 1956. 40. Langeland, K.: Tissue Changes in the Dental Pulp; An Experimental Histologic Study, Odontol. Tidskr. 65: 243-387, 1957. 41. Legros, C., and Magitot, E.: Greffes de follicules dentaires et de leurs organes constitutifs insoliment, anaerobies d’origine bucco-dentaire, Rev. Stomatol (Paris) 73: 2 I-30, 1972. 42. Lenwodt, K. W.: aber das Wesen der Allergic, Dtsch. Zahn, Mund. Kieferheilkd. 49: 34-40, 1967. 43. Linden, L. A.: Microscopic Observations of Fluid Flow, Through Cement and Dentine: An in vitro Study of Human Teeth, Odontol. Revy. 19: 367-381, 1968. 44. Magnusson, B., Koch, G., and Nyquist, G.: Contact Allergy to Medicaments and Materials Used in Dentistry (I), Odontol. Revy. 21: 287-299, 1970. 45. Maksudov, M. M., and Dranovsky, G. E.: Experience in Allotransplantation of Dental Rudiments, Stomatologiia (Mosk.) 54: 62-65, 1975. 46. Mascrts, 5.: Etude Histo-Pathologique de l’fivolution des Pulpites chez les Animaux SensibilisBs, M&moire de Mditrise is Sciences (Biologie Dentaire), Fact&O de Mtdicine Dentaire, Universitk de Montrtal, 197 1. d&.

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47. Mascres, C., and Adamkiewicz, V. W.: Induction et Evolution d’une Pulpite Allergique chez le Lapin Sensibilise au Chloro-2,4-dinitrobenzene. I. Technique de Sensibilisation et du Transfert Passif, Revy Can. Biol. 30: 217-222, 1971. 48. Mascres, C., and Adamkiewicz, V. W.: Pulpite Allergique Experimentale chez le Lapin, J. Biol. Bucc. (Paris) 5: 149-157, 1977. 49. Mascres, C., Mezel, Z., and Adamkiewicz, V. W.: Pulpitis due to I-chloro-2, 4-dinitrobenzene in Sensitized Rabbits, J. Dent. Res. 50: 1687, 1971. 50. Mejare, B.: Srreptococcusfaecalis andStreptococcus faecium in Infected Dental Root Canals at Filling and their Susceptibility to Azidocillin and Some Comparable Antibiotics, Odontol. Revy 26: 193-203, 1975. 51. Mincer, H. H., and Jennings, B. R.: Morphologic and Immunologic Studies of Subcutaneous Incisor Allografts in Mice, J. Dent. Res. 49: 381-388, 1970. 52. Mitscherlich, A.: Sur IaTransplantation et la Reimplantation des Dents, Arch. GCn. de Med. 1: 876, 1864. 53. Mjor, I. A.: The Penetration of Bacteria into Experimentally Exposed Human Corona1 Dentin, Stand. J. Dent. Res. 82: 191-196, 1974. 54. Myers, H. L., and Flaungan, V. D.: A Comparison of Results Obtained from Transplantation and Replantation Experiments Using Syrian Hamster Teeth, Anat. Rec. 130: 497-5 13, 1958. 55. Nisengard, R., Beutner, E., and Hazen, S. P.: Bacteria1 Hypersensitivity and Periodontal Disease, J. Periodontol. 39: 46, 1968. 56. Novak, L., and Merker, H. J.: Das Electronenmikroskopische Bild der Zahnpulpa nach Unterbrechung der Blutpirkulation, Dtsch. Zahnarztl. Z. 25: 1078-1083, 1970. 57. Okada, H., Aono, M., Yoshida, M., Munemoto, K., Nishida, O., and Yokomizo, I.: Experimental Study on Focal Infection in Rabbits by Prolonged Sensitization through Dental Pulp Canals. Arch. Oral Biol. 12: 1017-1034, 1967. 58. Olgart, L., Brannstrom, M., and Johnson, G.: Invasion of Bacteria into Dentinal Tubules. Experiments in viva and in vitro, Acta Odontol. Stand. 32: 61-70, 1974. 59. Pafford, E. M.: Homogeneous Transplantats of Preserved Frozen Teeth, ORALSURG.9: 55-70, 1956. 60. Paterson, R. C.: Bacterial Contamination and the Exposed Pulp, Br. Dent. J. 140: 231-236, 1976. 61. Pekovic, D. D.: Auto-allergic Experimentale de la Pulpe Dentaire, Mtmoire de Mditrise es Sciences, Faculti de Medecine, Universite de Montreal, 1976, p. 201. 62. PekoviC, D. D., Mascres, C., and Adamkiewicz, V. W.: Induction d’une Pupite Auto-allergique chez le Lapin, Pathol. Biol. (Paris) 25: 437-442, 1977. 63. Phillipeaux, J. M.: Greffe d’une Incisive de Cochon d’Inde dans la Crete d’un Coq, Compt. Rend. Sot. Biol. 1: 336, 1870. 64. Plies, G., and Pfiiger, H.: Homologous Tooth Transplantation and Tooth Development, Frankfurt Z. Pathol. 70: 246-270, 1959. Cited in Zaleski, M., Obersztyn, A., Rymaszewska-Kossakowska, T., Jedrzejczyk, J., and Stankowski, A.: Immunizing Properties of Allogeneic Dental Pulp Grafts in Rabbits, Transplantation 5: 589-596, 1967. 65. Policart, A.: Les Reactions Inflammatoires et Leur Dynamique, Paris, 1965, Masson, p. 169. 66. Pulver, W. H., Taubman, M. A., and Smith, D. J.: Immune Components in Human Dental Pulp and Periapical Lesions (abstract), J. Dent. Res. 55: B. 229, 1976. 67. Pulver, W. H., Taubman, M. A., and Smith, D. J.: Immune Components in Normal and Inflammed Human Dental Pulp, Arch. Oral Biol. 22: 103-I I I, 1977. 68. Robinson, P. J., and Rowlands, D. T.: Evidence of Immune Response to Orthotopic Tooth Allografts in Syrian Hamsters, Transplantation 14: 787-790, 1972. 69. Rocklin, R. E.: Mediators of Cellular Immunity. In Fudenberg, H. H., Stites, D. P., Caldwell, J. L., and Wells, J. V. (editors): Basic and Clinical Immunology, Los Altos, Calif.. 1976, Lange Medical Publications, p. 623. 70. Rosengran, L.: The Antibody Response to Experimental Streptococci Infection of the Dental Pulp of the Cat, Odontol. Tidskr. 20: 261-360, 1962. 71. Rost, A.: Histologische Pulpauntersuchungen Bei Zahnhals-Hypersensibilitat, Dtsch. Zahniirztl. Z. 22: 680-684, 1967. 72. Selipsky, H.: Chronic Periodontal Disease: A Review of Possible Immunopathology and the Validity of the Arthus, Shwartzman and Delayed Hypersensitivity Responses as Model Systems, J. Dent. Assoc. S. Afr. 26: 232-238, 1971. 73. Seltzer, S., and Bender, 1. R.: The Dental Pulp, ed. 2, Philadelphia, 1975. J. B. Lippincott Company. p. 165. 74. Slavkin, H. C., Trump, G. N., Mansour, V., Matosian, P.. and Mino, W. G.: Localization of Histocompatibility Alloantigens on Mouse Embrionic Tooth Epithelial and Mesenchimal Cell Surfaces, J. Cell. Biol. 60: 795-801, 1974. 75. Stanley, H. R.: The Effect of Systemic Disease on the Human Pulp. In Siskin, M. (editor): The Biology of the Human Dental Pulp, St. Louis, 1973, The C. V. Mosby Company, pp. 606-648.

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76. Strassburg, M., and Schtibel, F.: Generalisierte allergische Reakction durch Silberamalgamftillungen, Dtsch. Zahnarztl. Z. 22: 3-9, 1967. 77. Sulzmann, R.: Beitrage zur Histologie der Zahnpulpa. Il. Licht und Elektronenmikroskopische Darstellung von Plasmazellen und Gewebsmastzellen in Permanenten Monoradicularen Hundezahnen, Anat. Anz. 119: 202-208, 1966. 78. Swartz, M. L., Niblack, B. F., Alter, E. A., Norman, R. D., and Phillips, R. W.: In Viva Studies on the Penetration of Dentin by Constituents of Silicate Cement, J. Am. Dent. Assoc. 76: 573-578, 1968. 79. T&J, N., Fye, K., and Moutsopoulos, H.: Autoimmunity. In Fudenberg, H. H., Stites, D. P., Caldwell, J. L., and Wells, J. V. (editors): Basic and Clinical Immunology, Los Altos, Calif., 1976, Lange Medical Publications, p. 15 1. 80. Vojinovic, O., Nyborg, H., and Brannstrom, M.: Acid Treatment of Cavities Under Resin Fillings: Bacterial Growth in Dentinal Tubules and Pulpal Reactions, J. Dent. Res. 52: 1189-l 193, 1973. 81. Weinreb, M. M., Sharav, Y., and lckowicz, M.: Behavior and Fate of Transplanted Tooth Buds. Il. Low Antigenicity of the Tooth Bud Allograft, Transplantation 6: 289-293, 1968. 82. Weizenberg, J., and Bjedl, W.: Uber die Transplantation von Zahnkeimen. Der Nachweise des Auschlusses der Transplantaten an den Blutkraislauf des Wirts mit Hilfe von lsotopen. Ill. Mitteilung, Acta Anat. (Basel) 29: 291-296, 1957. 83. Wells, J. V.: Immune Mechanisms in Tissue Damage. In Fudenberg, H. H., Stites, D. P., Caldwell, J. L., and Wells, J. V. (editors): Basic and Clinical Immunology, Los Altos, Calif., 1976, Lange Medical Publications, pp. 225-241. 84. Wislocki, G. B., Singer, M., and Waldo, C. M.: Some Histochemical Reactions of Mucopolysaccharides, Glycogen, Lipids and Other Substances in Teeth, Anat. Rec. 101: 487-514, 1948. 85. Zachrisson, B. U.: Mast Cells in Human Dental Pulp, Archs. Oral Biol. 16: 555-556, 1971. 86. Zaleski, M., Obersztyn, A., Rymaszewski-Kossakowska, T., Jedrzejczyk, J., and Stankowski, A.: lmmunizing Properties of Allogeneic Dental Pulp Grafts in Rabbits, Transplantation 5: 589-596, 1967. 87. Zander, H. A.: The Reaction of Dental Pulps to Silicate Cement, J. Am. Dent. Assoc. 33: 1233.1243, 1946. Reprint requests to: Vincent W. Adamkiewicz Professor of Immunology Department of Microbiology and Immunology University of Montreal Montreal, H3C 357, Quebec,