0022-202X/85/850 ls-0 ll 5s$02.00/ 0 TliE J OURNAL OF INVESTIGATIVE DERMATOLOGY, 85:1 15s- 120s, 1985 Vol. 85, No. 1 Supplement Copyright © 1985 by The Williams & Wilkins Co. Printed in U. .A. Pathogenesis of Graft-Versus-Host Reactions (GVHR) and GVH-like Diseases ERNST GLEICHMANN, M.D. AND HELGA GLEICHMANN, M.D. Division of Immunology, Medico /Institute of Environmental Hygiene and Diabetes Research Institute, University of Dii.sseldor{, Dusseldorf, F.R.G. The graft-versus-host reaction (GVHR) in both mice causa ignota or after exposure to certain viruses or and humans can lead to the development of a broad drugs, are caused b y T lymphocytes reacting against spectrum of clinical and pathological symptoms. These self-MHC structures on lymphohemopoietic cells that symptoms are strikingly similar to those of a number of were rendered "foreign". By analogy to GVHD, it is diseases of proven or presumed immunolog ical origin, conceivable that the development of either stimulatory such as systemic lupus erythematosus (SLE), other col­ or suppressive GVH-like symptoms in individuals ex­ lagen vascular diseases, lymphoproliferative disease, posed to a given virus or sensitizing drug depends not and aplastic anemia. on the etiologic agent per se, but on whether the predom­ 8 The purpose of our investigation was to describe the inant r esponse is made by the individual's TH or T 1K immunological and pathological events that take place cells. This, in turn, might depend on whether the agent in the course of graft-versus-host disease (GVHD) and becomes immunogenic in combination with class-II or to gain insight into the cellular mechanisms underlying class-! alloantigens. these events. To this end, a model was employed in which nonirradiated F, mice were used as recipients of paren­ tal lymphoid cells. By pathological manifestations, 2 basic forms of GVHD can be distinguished in such non­ Lymphocytes are highly speciali zed in recognizing and re­ irradiated Ft recipients: One is acute GVHD which is sponding to foreign elements invading from the outside world often lethal. It is characterized b y a variety of suppres­ while no apparent, or at least no harmful , immune reactions sive (hypoplastic) pathological symptoms, including a develop towards self-constituents. Previously, it had been pro­ severe hypoplasia of the lymphohemopoietic system ac­ posed that t his state of self-tolerance is achieved by deletion of companied by aplastic anemia and hypogammaglobuli­ self-reactive clones during ontogeny a nd autoimmunity results nemia. The other basic form is characterized by stimu­ from the effect of "forbidden clones" [1] . From more recent latory symptoms, such as persistent lymphoid hyperpla­ experimental scrutiny, however, we know that potentially au­ sia, formation of autoantibodies, 'and development of toreactive B lymphocytes do exist in the intact, healthy immune pathological symptoms reminiscent of SLE and other system (2-8] but are normally controlled by mechanisms pre­ collagen vascular diseases. The suppressive pathological cluding a utoimmune reactivity. The designation autoimmune graft-versus-host (GVH) symptoms are caused by T sup­ disease is unambiguous where the functional relevance of auto­ 81 antibodies to unaltered autoantigens has been established, e.g., pressor/killer (T K) cells of the donor which react to­ antibodies reacting with t he acetylcholine receptor in myas­ wards allogeneic class-1-structures of the F 1 recipient's major histocompatibility complex (MHC). The stimula­ t henia gravis, with erythrocytes in autoimmune hemolytic ane­ tory pathological GVH symptoms, by contrast, are mia, with the insulin receptor in some patients with insulin­ caused by donor T helper (T'') cells which react toward resistant diabetes, with thyroglobulin in Hashimoto's thyroid­ the recipient's allogeneic class-II-MHC structures. itis, with basement membrane structures in Goodpasture's syn­ The possible implications of these observations for the drome, with the intrinsic factor in pernicious a nemia, or with pathogenesis of a number of GVH-like diseases in hu­ various a utoantige ns as in systemic lupus e rythematosus mans are discussed. The hypothesis is advanced that (SLE). Other di sease processes are also immunologically me­ some of these GVH-like conditions, which arise either e diated, alt hough they are not strictly autoimmune in t he sense that the immune reaction is directed to unaltered self-antigen. For instance, immune complexes that contain foreign material, Supported in part by a grant f~om Deutsc he Forsc hungsgemeinsc haft such as microbial antige ns, can cause deleterious lesions such (Hu 290/1), Bonn, Fede ral Republic of Ge rm any. as glomerulonephritis. Thus, in this type of immunological Rep rint requests to: Ern st Gleichmann , M.D., Division of Immunol­ disea e t he target antige ns need not consist of unaltered self­ ogy, Medical Institute of Environmental Hygiene, Un iversity of Dues­ antigens. Moreover, patients with aplastic anemia may have T seldorf, Auf'm Hennekamp 50, D-4000 Duesseldorf 1, Federal Republic lymphocytes that suppress t he growth of erythroid and myeloid of Germany. colonies in cultures [9,10] . Here, the eliciting antigen is not Abbreviations: ANA: antinuclea r antibodies' known at all. DPH: diphenylhyda ntoin To analyze the mechanisms of autoimmune diseases 2 ge n ­ dsDNA: doub le-stranded DNA era lly different types of experimental animal models have been GV H: graft-versus- host used: t hose in which the diseases occur spontaneou.sly and those GVHD: graft-versus-host di sease in which t he diseases are induced in recipients that usually GV HR: graft-ve rsus- host reaction(s) would not suffer from autoimmune attacks. The spontaneous ICGN: immune co mplex glome rulonep hritis lupu ~- lik e disease of New Zealand Black mice is a n example of MCH: major hi stocompatibi li ty complex the l!rst type. Vanous techmques have been applied for the MuLV: murine leukem ia virus e.xperi~ e ntal induction of aut?immuni PLN: popliteal lymph node ty: these include injec­ SLE: systemic lupus erythematosus tiOn of syngenetc or a ll ogenetc tissues mixed with Freund's T DTH ce ll : T cell ca usin g del ayed hyperse nsitivity reaction complete adjuvant into normal animals, manipulation of the Tg: thyroglobu lin lymphocyte population by thymectomy at a stage of immatu­ TH cell: T-helper cell ri ty, or modification of normal cells by chemicals and viruses. T51K ce ll: T-all osuppressor/ ki ll er ce ll The present paper fo cuses first on the well -defined cellula r 115s 116s GLEICHMANN AND GLEICHMANN Vol. 85, No. 1 Supplement pathogenesis of a s pectrum of immunologic diseases which can be induced b y T lymphocytes in ge neticall y normal mice undergoing systemic graft-versus-host reactions (GVHR). In t his model T lymphocytes are responding to allogeneic struc­ tures of the major hi stocompat ibility complex (MHC) (i.e., H - 2) . The second part of the paper deals with t he possible patho­ ge nic mechanism(s) of GVHR-like immunologic disorders which arise after exposure to a fore ign compound and might be due to graft-versus-host-(GVH) like reactions ofT lymphocytes towards self-structures rendered n on -self by the etiologic agent. GRAFT-VERSUS-HOST REACTIONS (GVHR) B DONOR Experimental Design GVHR was induced by injection of parental strain lympho­ .l>.l!R ..... cytes in to adult, otherwise untreated, F1 hybrid recipients. For rH _..---- ---- TS/K genetic reasons, t he grafted cells are tolerated and not rejected Lyt n- Lyt ,.2. by the semiallogeneic F, host. The injected T lymphocytes, t however, recognize alloantigens whi ch the F1 host has inherited Lyt ,-z· ........... ___________ ,. from the other parental strain. These a ll oreactive donor T ly mphocytes mediate the development of various immunologi­ soppress\of\ I cal lesions .' For t he induction of immunologic diseases by I GVHR 2 conditions are required: 1) all oreactive T lymphocytes It: rlo·- have to be present in the inoculum and 2) a histoincompatibility ,r:: .. has to be present in the F 1 recipient in order to activate the I'- donor T lymphocytes. In non irradiated F, mi ce, the histoincom­ I //., I patibility has to be provided by t he recipient's major histocom­ I patibility complex MHC, i. e., H-2 in t he mouse. Spec;l;rum of GVHR-Induced Immunological Disorders F1 RECIPIENT Fig 1A shows the spectrum of pat hological symptoms which can be induced by GVHR. The majority of t hese alterations han.: been observed as sequelae ofGVHR in both human (11,12] ~ I o I ana laboratory a nimals (12- 14] . Two basic forms of GVHR­ in duced pathological lesions have been distinguished. One form ·--- is characterized by stimulatory pathological symptoms, as shown H-2=mijor histocompitibility complex !MHC) in t he middle and on the left hand side o f Fig lA. These symptoms include a persistent lymphoid hyperplasia of mainly FIG l. Spectrum and co ncept of ce llular pathogenesis of immuno· B lymphocytes resul ting in hypergammaglobulinemia and the logical disorders resulting from GVHR in F, mice. Not listed is toxic formation of autoantibodies characteristic of SLE, such as epidermal nec rolysis which is a se rious GVH complication in species antibodies against nuclear antige ns (ANA), double-stranded other than mouse, such as hamster and man (see [1 2] for references). A, Spectrum of pathological lesions DNA (dsONA), erythrocytes, and thymocytes [3,15- 20]. In that. may develop in GVH F, mice. B, Co ncept of the basic cellular and MHC requirements for induction addition, stimulatory GVH symptoms include a severe immune­ of stimulatory and middle (left) and suppressive (right) GVHR lesions, complex glomerulonephritis (ICG N) in which antibodies respectively.