Histocompatibility-Linked Genetic Control of Specific Immune Responses to Viral Infection

Transplant. Rev. (1974), Vol. 19 209-225

Published by Munksgaard, Copenhagen, DenmarkNo part may be reproduced by any process without written permission from the author(s)

Histocompatibility-Linked

Genetic Control of Specific Immune

Responses to Viral Infection

HUGH O. MCDEVITT*, MICHAEL B . A. OLDSTONE & THEODORE PINCUS

I. INTRODUCTION

During the past several years, it has become apparent that the specific immuneresponse to a wide variety of synthetic polypeptides, protein antigens, andmany isoantigens is under genetic conrol (McDevitt and Landy 1972). Inmost instances, control of specific immune responses has been shown to belinked to the species' major histocompatibility locus in the mouse, the guineapig, the rat and man (Benaeerraf and McDevitt 1972, Levine et al. 1972).In the mouse there have also been several reports of associations between H-2type and susceptibility or resistance to lymphocytic choriomeningitis virusinfection (Oldstone et al. 1973) and leukemia virus-associated disease (Lilly& Pincus, 1973). It appears that these associations between H-2 type andresistance or susceptibility to viral-induced processes is mediated via themechanism of an //-2-linked specific immune response (/r) gene, althoughthis has not been definitively demonstrated. The evidence that histocomp-atibnity-linked specific immune response genes are important genetic fectorsin controlling resistance or susceptibility to viral infection will be briefly re-viewed here. As pointed out by Snell (1968), there are several possible

The Division of Immunology, Department of Medicine, Stanford University Schoolof Medicine, Stanford, Ca. 94305; The Department of Experimental Pathology, ScrippsClinic & Research Foundation, La JoUa, Ca. 92037; and The Sloan.-Kettering Institutefor Cancer Research, 410 East 68th Street, New York, N.Y. 10021.Research supported by US Public Health Service grants: AI 07757, AI 09484, AI 07007and CA 08748.* H. O. M. was Senior Investigator of the Arthritis Foundation.Senior Investigator of the Arthritis Foundation.This is publication number 781 from the Department of Experimental Pathology, ScrippsClinic and Research Foundation.

Transplant. Rev. (1974), Vol. 19 i"

210 McDEVITT, OLDSTONE & PINCUS

reasons for associations between histocompatibility antigens and susceptibilityto specific viral infections: (a) the histocompatihility antigen may act as areceptor for a particular virus on the cell surface; in this case susceptibilitywould be expected to be a dominant trait in the heterozygote. (b) A histo-compatibility antigen may cross-react with a major antigenic determinant ona virus protein coat and lead to tolerance of the host toward the invadingvirus; once again susceptibility would be expected to be dominant in theheterozygote. (c) The close association between the major histocompatibilitycomplex in mouse and man and genes affecting specific immune responsesmay govern the relation of the histocompatibility type and response to virus;in this case, resistance would be expected to be dominant in the heterozygote,since H-2-linked Ir genes are dominant.

The wide variety of histocompatibility-linked specific immune responsegenes in several species (McDevitt & Landy 1972, Benacerraf .& McDevitt1972) makes it natural to suspect that specific anti-viral immune responsesmight be under this type of genetic control. The main purpose of this reviewis to describe two examples which fit this possibility, with the goal of stimula-ting virologists in the direction of searching for and analyzing this type ofgenetic control of specific anti-viral immune responses both in experimentalanimals and in man. The review wiU be restricted to covering two clearlydocumented cases in mice, lymphocytic choriomeningitis and murine leukemiavirus infection. It shotild also be noted that there are other types of geneticcontrol of specific immune response (reviewed in McDevitt & Landy 1972)and there is reason to think that some of these types of genetic controls willalso be implicated in specific anti-viral immune responses. However at thepresent time the available evidence indicates that immune responses to com-plex viral antigens, under a recognized type of genetic control, are most likelyto be under histocompatibility-linked specific Ir gene control.

n. HISTOCOMPATIBILITY-LINKED SPECIFIC IMMUNE RESPONSE GENES

The current state of the experimental analysis of histocompatibility-linkedspecific immune response genes has been extensively reviewed - (McDevitt &Landy (1972), Benacerraf & McDevitt (1972), and only the major charac-teristics of Ir genes are listed here (Table I).

It has been postulated that this type of Ir gene controls the structure and/orfunction of antigen specific receptors on the surface of thymus derived lympho-cytes, based on several lines of evidence in both the guinea pig and the mouse(McDevitt & Landy 1972, Sessions 1 and 2): a) the B-ceU product, i. e. anti-body is identical in specificity, affinity, and isoelectric focusing characteristicsin responder and nonresponder animals, b) Ir genes control T-cell functions

ROLE OF SPECIFIC IMMUNE RESPONSE GENES 211

TABLE IMajor Common Charateristics of Histocompatibility-Linked

Specific Immune Response Genes

1. Antigen specific.2. High response is an autosomal dominant trait.3. Qualitative, and in some cases large quantitative differences in the level of the hu-

moral antibody response.4. Transferable with immunocompetent cells.5. Linked to the species' major histocompatibility complex.6. These genes control the humoral antibody response and also control 'pure' T cell

function including delayed hypersensitivity, antigen induced tritiated thymidine up-take, and graft rejection.

as well as the humoral antibody response, c) these genes are antigen-specific,d) a variety of maneuvers which are designed to substitute for specific T-cellhelper activity, i. e., the use of additional 'carrier' molecules, such as acetyl-ated or methylated bovine serum albumin, or the use of an allogeneic effect,are successful! in converting a non-responder animal to responder status.

For example, nonresponder guinea pigs will make anti-DNP poly-L-lysineantibody of the same specificity as responder guinea pigs if they are immun-ized with DNP-poly-L-lysine electrostatically complexed with acetylatedbovine serum albumin (Benacerraf, Session 1, McDevitt & Landy 1972).Grumet (1972) has shown that responder and nonresponder mice have thesame 19S primary antibody response to acqueous (T, G)-A—^L (a branchedsynthetic polypeptide composed of tyrosine, glumatic acid, alanine and lysine).However, only the responder strains exhibit a 7S secondary antibody responseto a second injection of this antigen and this 7S secondary response is abolish-ed by the thymectomy of the responder strains. Thymectomy has no effect onthe nonresponder strain (Mitchell et al. 1972). From This experiment, it canbe concluded that initial recognition and 19S antibody response to (T, G)-A—L are equal in the responder nonresponder strains and it is the thymus-dependent 7S secondary antibody response which is lacking in the non-responder strain. The most recent evidence which indicates, but does notconclusively prove, that histocompatibility (H)-linked specific Ir genes affectT-cell-specific antigen recognition is given in Benacerraf (in press 1974) andMcDevitt et al. (in press 1974). The exact mechanism by which these genesaffect T-cell antigen recognition (if this is their mechanism of action) is notyet clear. The continuing controversy over whether specific antigen receptorson T-cells are immunoglobulin in nature (Lisowska-Bernstein et al. 1973)has not yet been resolved but is obviously of critical importance in under-standing the mechanism of action of H-linked specific Ir genes.


The precise genetic relationship between the H-linked Ir genes and themajor histocompatibility complex is shown in Figure 1.

Figure 1. Genetic

Complex

Ends

Regions

Subregions

Loci

map of H-T complex.

K

H-2K

Ir-IA

IMA

H-2

K

1

Ir-IB

ir-IB

D

S

Ss.Sip

D

H-2D

H-21

[From: Klein et al. (1974)]

The major histocompatibility complex in the mouse is approximately 0.5map units in length and includes the H-2K and H—2D loci which control themajor serologically defined transplantation antigens which are active in elicitinganti-H-2 antibody, and graft rejection. In the middle of the complex is theSs-Slp locus which governs the level and aUotype of a serum alpha globulin,and between the H-2K and Ss-Slp loci are at least two genes or genetic re-gions controlling the specific immune response to a wide variety of syntheticpolyeptides, proteins, and isoantigens. These two loci are designated as Ir-IAand Ir-IB.

Mixed in this region between H-2K and Ss-Slp are a variety of other func-tions which are of considerable biological importance and which may or maynot be identical with the Ir-1 loci. These include genes controlling the struc-ture of antigens which elicit the mixed lymphocyte culture reaction in vitroand the graft vs. host reaction; genes which appear to be responsible for re-cognition events in the in vitro generation of cell-mediated cytotoxicity; andgenes controlling the structure of antigens which are found on B-cells andperhaps on T-cells (David et al. 1973) which have been designated as Ia anti-gens for Ir region associated antigens. The exact function of these antigensis not yet clear, although it has been postulated (McDevitt et al. 1974) thatthey may function in cell-cell interaction between T-ceUs and B-cells in thecourse of the induction of a specific immune response. While linkage ofspecific 7r-genes to the major histocompatibility complex has been establishedin the rat, the guinea pig, and in man, more precise genetic localization of theIr genes in relation to the major histocompatibility loci has not yet been


accomplished. Particular emphasis has been placed on the map position ofthe Ir gene in the mouse, because this is one way in which identity betweenIr genes and susceptibility or resistance to specific viral infections can eitherbe excluded, or made much more likely, using standard genetic mapping tech-niques (McDevitt et al. 1972). With this brief introduction into the natureand major characteristics of the histocompatibility-linked specific immuneresponse genes, we can now examine the evidence that tbese genes influencesusceptibility to specific viral infections.

III. LYMPHOCYTIC CHORIOMENINGITIS VIRUSINFECTION IN MOUSE

Tissue injury accompanying infection with lymphocytic choriomeningitis(LMC) virus in dependent upon the inoculum of virus, tbe immune responsemounted by the host against the virus, the interaction of virus and/or viruscoded antigens with the host's immune response, and the consequences ofthat interaction. Adult mice infected intracerebrally with a large dose of LCMvirus suffer a fatal acute disseminated necrotizing inflammatory disease (Arm-strong & LiUie 1934, Traub 1936, Rowe 1954), while mice infected in uteroor birth carry large amounts of virus in their blood and tissues throughouttheir life and develop a chronic progressive disease (Oldstone & Dixon 1969,1970 b, 1972). The tissue injury and resultant disease associated with LCMvirus infection is caused by the host's immune response to the virus. First,only adult mice capable of mounting an immune response against LCM virusdevelop an acute fatal disease when challenged with virus. Immunosuppressioninduced by several methods prevents acute disease in adult mice despite ade-quate viral replication (Rowe 1956, Haas & Stewart 1956), Hotchin & Weig-and 1961, East et al. 1964, Hirsch et al. 1967, Lundstedt & Volkert 1967,Gilden et al. 1972 a, b). Second, parabiosis of, or spleen cell transfer from, miceimmunized against LCM virus to chronically infected isologous recipientsinitiates and/or intensifies the tissue injury associated with chronic LCM virusinfection (Oldstone & Dixon 1970 a). In addition, the transfer of isologous,homologous or heterologous anti-LCM antibody to chronically infected miceresults in acute necrotizing inflammatory lesions in regions of viral persistencefollowed by mononuclear infiltrates (Oldstone & Dixon 1970 a). Third, detect-able cellular injury occurs in tissue cultures infected with LCM virus onlyfollowing the addition of either antibody LCM virus and complement (Old-stone & Dixon 1971, Cole et al. 1973), or isologous immune lymph node orspleen cells (Lundstedt 1969, Oldstone et al. 1969, Oldstone & Dixon 1970 c.Cole et al. 1972, Wright et al. 1972, Marker & Volkert 1973).


While the itnportance of the immune response is well appreciated, therelative roles of serum antibody, circulating virus-antiviral antibody com-plexes and sensitized cells have not been delineated. In acute infection, serumantibody against virus, virus-antiviral antibody complexes and sensitized cellsare present and capable of eliciting tissue injury (Oldstone & Dixon 1970 d).Adult thymectomized and lethally irradiated mice and nude (thymusless) miceare highly susceptible to an ordinarly lethal inoculum of LCM virus whenreconstituted with sensitized T cells and normal B cells and less susceptiblewhen reconstituted with sensitized B cells alone (Oldstone, unpublished ob-servations). The further participation of anti-viral antibody effects mediatedby the activating complement system can be seen in in vivo experiments whenmice treated with cobra factor are protected from the ordinarOy lethal effectsof LCM virus challenge while showing no deficiency in either infectious virusreplication or loss of activity of sensitized lymphoid cells (Oldstone & Dixon1971 a). Cobra factor, which depresses C3 levels, inhibits the antibody-com-plement activating system while sparing delayed sensitivity reactions (Coch-rane et al. 1970). The evidence for cell mediated injury can be seen in thoseexperiments in which adult immunosuppressed mice do not succumb to anordinarily lethal dose of LCM virus, but will develop acute central nervoussystem disease when transfused with sensitized lymphoid cells, specifically Tcells (Cole et al. 1972, Gilden et al. 1972 a,b). In in vitro experiments, tissueculture cells infected with LCM virus can be injured when mixed with sensit-ized T cells (Cole et al. 1973, Marker & Volkert 1973, Oldstone, unpublishedobservations). Further, sensitized lytnphoid ceUs can be shown to release, byimmunologically specific means, both lymphotoxins (Oldstone & Dixon1970 c) and macrophage migration inhibition factor(s) (Tubergen & Old-stone 1971).

Mice naturally infected in utero or inoculated with LCM virus shortly afterbirth carry high titers of virus in their blood and organs and mount an anti-viral humoral and cellular response throughout life (Oldstone & Dixon 1969,1970 b, 1970 d, 1972, Oldstone 1973). Such persistently infected mice devel-op an associated chronic disease consisting of glomerulonephritis, arteritis,focal hepatic necrosis, immune complex deposits in the choroid plexus, exten-sive lymphoid proliferation and interstitial round cell infiltrations in manyof the body's tissues. The development of disease is directly related to theamount of LCM virus carried, the size of the anti-LCM immune responsemade, and interaction between virus and antibody. Parabiosis of immune micewith, or transfer of immune lymphoid cells to, or passive transfer of antibodyto, persistently infected isologous mice initiates or intensifies the manifesta-tions of chronic disease. Immunopathologic study of the injured target organsclearly indicates that chronic disease is due to immune complex deposits of


virus and anti-viral antibody. There is general T cell competence in micechronically infected with LCM virus (Oldstone & Tishon 1970, Oldstone1973) and as yet, no experimental evidence for suppression of T cells (Old-stone, unpublished observations).

The severity and time of onset of disease associated with chronic LCMviral infection varies greatly among strains of mice. Early studies showedthat those strains with the greatest amount of virus and the most antibodydeveloped the earliest and the most severe disease (SWR/J, C3H.0, DBA/1),while the C3H/HeJ, C3H/St and C57BR/cd strains with least virus and lessantibody had less detectable disease over a two-year observation period.Following infection at birth, in the most susceptible strain's immunoglobulin,accumulations in the glomeruli can be detected by 3 weeks of age and histo-logically evident kidney, liver and lymphoid disease by 6—8 weeks of age.The finding of chronic LCM disease with varying severity in different strainsof mice (Oldstone & Dixon 1969) resolved a scientific disagreement amongearlier workers. Baker & Hotchin (1967) who described renal disease withchronic LCM infection worked with a Swiss albino random bred strain whichis probably closely related to the inbred SWR/J strain, whereas Volkert(1964), who did not observe disease in carrier mice, worked with C3H/HeJand AKR/J strains.

Similarly, in acute LCM infection of adult mice there is variation in strainsusceptibility. As with chronic LCM infection, we observed that those stransthat were H-2i (i. e., SWR/J, C3H.0, DBA/1 were highly susceptible toLCM disease, whereas those strains that were H-2^ (i. e., C3H/HeJ, C3H/ST,C57BR/cd) were significantly more resistant. To clearly define the relation-ship of H-2'' and H-2^' aUeles to acute LCM virus disease (Oldstone et al.1973), we compared the susceptibility of C3H.O mice with that of C3H/HeJmice. C3H.0 are congenic with C3H/HeJ mice, differing only at the H-2complex, C3H.Q being i?-2«''«' whereas C3H/HeJ are H-2'"'^'. The amountof LCM virus needed to kill 50 per cent of the C3H.0 mice was significantlyless than the amount of LCM virus needed to kill 50 per cent of the C3H/HeJ mice. Further experiments clearly showed that susceptibility to acuteLCM virus disease is controlled in part by dominant genes closely linked tothe H-2 locus (Oldstone et al. 1973). In studies involving the SWR/J (H-2^'^), C3H/HeJ (H-2''^), their Fi hybrid and the reciprocal backcrosses, wefound that 1) the Fi hybrid from mating a susceptible mouse to a resistantmouse is susceptible to LCM virus disease, 2) when such hybrids are back-crossed with susceptible parents all backcross offspring carry an H-2'' allele,that is, H-2''"' and H-"^^, and are highly susceptible, whereas backcross toresistant parents resulted in half o fthe F2 offspring being susceptible (H-2^^^)while the other half are relatively resistant (H-2^^^). (Table II) Although the


TABLE IIRelationship of q and k H-2 Alleles in Susceptibility to Acute LCM Disease*

H-2 Sex*No. of mice

Injected LCMdisease***

Mortality

Fj X SWR/J

F^ X C3H/HeJ

qlkqlkqlqqlq

q/kqlkkikkik

MFMF

MFMF

22181220

12151720

17158

12

101074

77836660

83664120

* 1 X LD76 dose (for SWR/J mice) of L929 cell-passed virus was inoculated i.e. intovarious groups of mice. All mice were car coded, and 11-2 type was not known until theconclusion of the experiment.

** M, male; F, female.*** Deaths due to the disseminated, necrotizing, inflammatory effects of LCM virus

infection. Mice observed for 28 days after viral inoculation.(From: Oldstone et al. 1973).

backcross experiments were statistically highly significant, segregation in theFiXC3H/HeJ population did not show a strict 1 : 1 ratio, suggesting thatsusceptibility to LCM virus is multigenic.

Experiments were performed to determine whether histocompatibility anti-gens might represent specific receptor sites for attachment of LCM virus, orwhether histocompatibility antigens and LCM virus might share antigenicdeterminants (Oldstone et al. 1973). In a series of experiments in which infec-tious virus was added to either C3H.Q or C3H/HeJ mouse embryo cells,approximately 1 per cent of the total infectious virus was absorbed to eitherculture line, indicating that cells from the H-2^ mice absorbed the sameamount of LCM virus as did H-2^ cells. If histocompatibility antigens andLCM virus shared the same determinants then the host would fail to respondimmunologically to the virus. Hence, the host should exhibit complete resis-tance from injury associated with LCM virus infection as tissue injurydepends on an effective immune response. This was not the case, as bothsusceptible and resistant strains are capable of mounting humoral and cellularresponses against the virus and »resistant* mice succumb to LCM viral infec-tion. In addition, antibody made against H-2* determinants does not stainother culture cells infected with LCM virus.

Hence, all of the above data strongly suggest that an immune response gene


analogous to the. Ir gene described by McDevitt & Benacerraf (1969) controlsthe ability of the host to respond to LCM viral antigen(s). Reasons for be-lieving that this is so are: 1) Since the H-2 linked immune response genes aredominant, susceptibility would be expected to be and is dominant in the hete-rozygote. Mice that are homozygous or heterozygous for //-2« are susceptible,whereas those homozygous for H-2'' are resistant. 2) Inflammatory responsesmounted in the injured target tissues in vivo against the virus by H-2'' micewere greater than those of H-2'' mice, yet the amounts of virus carried in thetarget tissues were similar in mice of both H-2 types.

The natural host variation in the ability to resist infectious diseases is avery complex process affected by immune and non-immune mechanisms. Theevidence so far suggests that LCM virus infection represents an example ofhistocompatibility linked genetic control of specific disease susceptibility.However, there are experimental points that need to be established beforeLCM virus infection can be clearly established as an example of a histo-compatibility linked Ir gene immune response disease. First, there is as yetno solid quantitative data on either the cellular or humoral response made byresistant or susceptible strains. Hopefully, techniques that will quantitate invitro cell mediated injury as well as new techniques that will directly measureantibody forming cells to the virus will soon be available. Second, it is not yetknown whether the distribution or the concentration of viral antigen on thecell surface is different in the susceptible (H-29) or resistant (H-2'') cells.Third, the activation of pharmacologic mediators of tissue injury may begreater in H-2'' than H-2" cells. Future experiments should shed light on theabove points, while the use of other strains bearing recombinant H-2 chromo-somes should better map the locus responsible for H-2 linked susceptibilityto LCM.

Nevertheless, our results have implications for those studies attemptingto explain relative susceptibility in other diseases of man or animals in whichthe immune response plays a dominant role. In particular, infection of a hostby a virus offers opportunities for the development of immune pathologicinjury. The virus as a self replicating agent provides a continuous supply ofmacromolecular antigen, and in most if not all instances elicits a host immuneresponse. It is the interaction of these antigens with the host immune responsethat causes the tissue injury observed. Particular interest is centered on thosechronic viral infections in which both a continuous immune response againstthe virus and ongoing virus replication occur. These events are seen in humanitifections with rubella virus, cytomegalovirus, measles virus, Australia anti-gen, and in a host of animal diseases such as murine infections with lacticdehydrogenase virus and the oncomaviruses, mink infection with Aleutiandisease virus, and equine infection with equine infectious anemia virus. (Not-


kins et al. 1970, Oldstone 1974; and Oldstone & Dixon, 1971 b). Perhaps inmany of these diseases, genes which aflect specific immune responses may decidethe severity of the accompanying infection. Other viral infections that bearstudy are measles virus and mumps virus infections associated with anti-thyrogjobulin responses and thyroiditis, influenza virus and Parkinson-likedisorders, and finally, measles virus, T and B cell specific immune responses,and association with specific (HL-A) human transplantation antigens inmultiple sclerosis. (Jersild et al. 1973). Finally, LCM virus belongs in thearenovirus class of viruses in which at least two, Machupo and Junin viruses,cause acute hemorrhagic fever in man (Johnson et al. 1973). Similarities withLCM virus suggest that these disordes might also be immune response dis-eases under genetic control.

IV. THE ASSOCIATION BETWEEN H-2 AND VIRAL LEUKEMOGENESISIN THE MOUSE

The recognition of the role of genetic control in murine leukemogenesisderives initially from the development of high leukemia mouse strains, notablyC58 (Richter & McDowell, 1929) and AKR (Furth et al. 1933). Mice of thesestrains develop a thymic lymphoma with an 85 per cent incidence. The dis-ease is ablated by early thymectomy, and it is noteworthy that the thymocyte(T cell) appears to be the target cell for the virus in nature (Gross 1970).Large scale studies of hybrids of high and low leukemia strains indicated asignificant correlation between leukemia incidence and the amount of geneticmaterial derived from the high leukemia ancestor (see Law 1954). However,no evidence of Mendelian ratios was found, and further understanding ofgenetics in relation to mouse leukemia was limited.

With the discovery of murine leukemia viruses (MuLV's) (Gross 1951), thevirus as a marker enabled identification of specific murine genes which controlcertain steps in the leukemogenic process, including: (a) viral expression -the Akv-1 and Akv-2 genes (Rowe 1972, Rowe & Hartley 1972, Rowe et al.1972); (b) viral replication - the Fv-1 gene (Lilly 1967, Pincus et al. 1971 a,b, Rowe et al. 1973), and (c) resistance to Gross virus and virus-transformedcells - the Rgv-1 gene (Lilly et al. 1964, LiUy 1966, Sato et al. 1973). TheAkv and Fv-1 genes do not directly affect the immune response and will notbe considered further here (see Lilly and Pincus 1973). This analysis indicatesthat a multigenic phenomenon can be dissected into component parts withappropriate markers.

The Rgv-1 locus does not affect viral replication, but rather later diseasepatterns, which led to the inference that the mechanism might involve theimmune response to the virus or to virus-transformed cells (Lilly et al. 1964,


Lilly 1966). The experiments leading to the recognition of Rgv-1 were sug-gested by the observation of Gorer (1959) that high leukemia mouse strains(AKR, C58, C3H/Figge and RF), as well as the two strains utilized by Gross todemonstrate a filterable agent from AKR mice, C3H/Bi and C57BR, are all ofthe H-2'' type. From these initial studies, it appeared that some relationexisted between susceptibility to leukemogenesis and the H-2'' type. In formalgenetic studies of mice of various H-2 types and their hybrids, neonatal micewere inoculated with Gross virus and observed for development of leukemiaby Lilly. The most extensively studied hybrids were those between C3H/Bi(H-2'') and C57Bh/6(H-2'>); in Fa and backcross hybrids, mice of the homo-zygous H-2*/* type showed a greater than 90 per cent incidence of leukemia,whereas H-2^^^ and H-2''''' mice showed a leukemia incidence of approx-imately 20 per cent, which was delayed in onset (Lilly et al. 1964, Lilly 1966).

Other lines of evidence indicate the relative susceptibility to viral leukemiaof mice of the H-2'' type, in contrast to the relative resistance of H-2'> mice.Tennant & Snell (1968), studying leukemogenesis by the B/T-L virus, ob-served a considerably greater level of resistance in the H-2'' C57BL/10 thanin the congenic ff-2* BIO.BR mice. AKR mice rendered congenic at H-2 byintroduction of the H-2'' allele from the C57BL/6 strain show a much delayedincidence of spontaneous leukemia (Boyse et al. 1972). A convincing exampleof the effect of H-2 on leukemia incidence involves a finding regarding thehost-range of radiation leukemia vims (RadLV) (Lieberman & Kaplan 1959),derived from the H-2^ C57BL/Ka mouse. When RadLV is inoculated intomice of the C3H (H-2'') and the congenic C3H.SW (H-2'') strains, leukemiaincidence is approximately 30 per cent in C3H and less than 10 per cent inC3H.SW, despite the fact that the virus itself was derived from an H-2'' mouse(Kaplan 1967). These data indicate that both strains are relatively resistanto leukemogenesis by the RadLV; this resistance appears to be a function ofthe Fv-1 gene, since both C3H and C3H.SW are Fv-i" mice, which wouldrender them resistant to the B-tropic RadLV (see Lilly and Pincus, 1973).The difference in the degree of resistance in C3H and C3H.SW is statisticallysignificant, and is of considerable interest when one considers associationbetween human leukocyte antigens HI^A and specific disease entities. In theexperimental animal model it is clear that H-2 linked resistance to leukemo-genis is only one of several genes determining resistance or susceptibility tothe leukemogenic process. For this reason the association between H-2* andsusceptibility, and H-2'' and resistance is partial so that only a portion of theH-2* mice develop viral leukemia and a smaller but finite proportion of theH-2'' mice also develop leukemia. When we consider the complexities intro-duced in studying a random breeding population which must include manyheterozygotes, it is clear that even partial associations of histocompatibility


antigens with specific disease entities may have considerable biological signi-ficance. This type of experimental animal model can thus be applied to similarfindings in man where associations between human leukemia and autoimmunedisease (see Rogentine et al. 1972, McDevitt and Bodmer, 1972). If analogsof the Akv and Fv-1 gene exist in humans, as is the case for the closelyanalogous H-2 and HU-A systems, they may remain unrecognized. If this isthe case, identification of partial associations with HL-A and susceptibilityor resistance will permit initial dissection of genetic susceptibility and mayincrease the possibility of discovering other unrelated genes which also in-fluence susceptibility.

Recent extension of knowledge of the relation of H-2 and Rgv-1 to thestudy of leukemia viruses is derived from experiments describing the X.Isystem (Sato et al. 1973). Certain leukemias derived fro BALB/c mice werefound to be rejected by hybrids of BALB/c with other inbred strains, contraryto the usual rules of transplantation. A prototype hybrid which showed rejec-tion was the BALB/cXC57BL/6(H2*;FI hybrid. Studies of several hybridsutilizing standard genetic tests established that the responsiveness to thesetumors was linked with the K region of H-2, the location of the Rgv-1 locus.The linkage of Rgv-1 to H-2 is of particular interest, in view of the findingthat a major murine immune response gene, Ir-1, is also linked to H-2 andmaps near the K region (McDevitt et al. 1972). The close association of H-2,Rgv-1 (X.I), and Ir-1 in linkage group IX emphasizes the importance ofthis chromosomal region in murine lymphoid immunobiology and neoplasia(see Boyse et al. 1972). The fact that resistance to viral leukemogenesis isdominant in the Fi hybrid fits with the hypothesis that the association betweenH-2 Rgv-1 and X.I is mediated via the mechanism of an H-2 linked specificimmune response gene, in that the immune response is thought to inhibitneoplastic disease. However it must be emphasized that, although the corre-lations between resistance and antibody titer and susceptibility and lack ofantibody titer suggest the effect of a specific immune response gene, that thishas not been proven. In particular there is as yet no good assay for cell medi-ated immunity to virus induced specific tumor antigens. In the absence of suchan assay it is difficult to immunize animals and show that the quantitativeimmune response to a specific tumor is different in congenic strains differingat the H-2 complex; thus it may be concluded that the hypothesis is not yetproven, although highly likely. Continuing analysis of the Rgv-1 and X.Igenes promises to provide a useful model for understanding the close relation-ship between viral genome, specific immune response, and the host's geneticbackground in the course of viral leukemogenesis in the mouse.


V. CONCLUSION

The studies cited here really only serve as indications of the potential rolethat specific immune response genes may play in the interaction between hostand virus. The major purpose of this review is to indicate the nature of thisrole, and to stimulate a further search for the role of specific immune responsegenes in the immune response to viral infection.

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Transplant. Rev. (1974), Vol. 19

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Histocompatibility-Linked Genetic Control of Specific Immune Responses to Viral Infection