e r o s , .d ea}ures
#nmunology Today, Vol. 11, No 7 1990
Sandoz Prize: T-B collaboration
JacquesMiller The inaugura!SandozPrizeforlmmunology has been awarded to Drs Max Cooper of the University of Alabama, Birmingham, and Jacques Miller of the Walter and Eliza Hall Institute in Melbourne. The prize, presented at the AAI meeting in New Orleans in June, recognizes the contributions
competence, seminal work on T-B cell cooperation and insights into the function of CD4 and CD8 in T-cell activation. Max Cooper and colleagues were the first to establish that the immune system can be divided, developmentally and functionally, into B- and T-cell populations. He has contributed substantially to the understanding of B-cell ontogeny, the mechanismsand treatments of B-cell immunodeficiencies and the processes governing the development of B-cell neoplasms. The prize of $100 000 will henceforth be awarded biennially, with the winners selected by a prestigious international jury. The aim of the MaxCooper prize is both to honour achievement in immunology and to encourage of the winners to the elucidation further research. The latter is reof B-cell (Coopar) and T-cell (Miller) flected in the use of the winnings: biology. Jacques and Max will use 80% to Each has exerted a great influence fund further research. on his chosen field. Jacques Miller's achievements include the origina! Richard Gallagher demonstration of the ~-oleof the ti~ymus in the development of immunoEditorof ImmunologyToday.
Heat shock proteins: immunity and immunopathology ......
to endosomal and surface membranes of macrophages and B cells, but was not found on T and natural killer (NK) cells. A fundamental role for this particular hsp70 could be to prevent total degradation of the pepfrom PeterM. Lydyardand Willem van Eden tide within endosomes and to carry the peptides to the surface for coassembly with class II (and class I?) Much interest has been generated in heat viewed by D. Young, London). Pro- MHC molecules. shock proteins (hsps)since they were im- karyotic hsps of these families share plicated as dominant antigens of infec- as much as 60% homology with Immunityto heat shockproteins During infection, hsps are induced tious microorganisms and suggested to mammalian forms at the amino acid have a role in the development of adju- level. They occur constitutively but in both microorganisms and host vant arthntis (AA) in rats. Advancesin the can also be induced by a variety of phagocytes. The dominant antigens understanding of the role of hsps in im- stress conditions. !hey function as of intracellular microorganisms are 'molecular chaperones' (J. Ellis, Warmunity and immunopathology were re- wick) which are defined as proteins hsp65 and hsp70. Cloned 'autoreactive' T cells have been obtained from cently discussed at a meeting held in that mediate corrc.ct folding of other normal donors for human hsp65 and Utrecht*, as part of the European Com- proteins and, in so.me cases, their hsp70 (D. Young). Could such T cells munity concertedaction on immunopatho- assembly into oligomeric structures. damage 'stressed' cells? In fact, virally genesis and irnmunotherapy of chronic A constitutive member of the infected, gamma-interferon (IFN-~/)-or art,hritis. hsp70 family is involved in anti- heat-treated macrophages were killed gen processing and presentation by T cells from M. leprae infected Heat shock proteins can be divided (S. Pierce, Evanstown). Using anti- mice recognizing conserved epitopes into four major families, with mem- immunoglobulin covalently coupled of hsp65 (S. Kauffman, Ulm). bers of molecular mass of about to cytochrome c and murine B cells Previous studies have suggested a 90kDa, 70kDa, 60kDa and 10- as antigen-processing cells, it was role for ~/~ T cells in mycobacterial 30 kDa. Most of the discussionat the shown that small peptides of the anti- disease. In vitro stimulation of blood T meeting revolved around the 60 kDa gen can be detected intracellularly cells with M. tuberculosis extract inand 70 kDa family members (re- attached to a 72-74 kDa peptide- creased ~/a T cell numbers (S. Kauffbinding protein within minutes. man). However, this effect was not *The mini-symposiumon HeatShockPro- Antibodies to this 72-74 kDa hsp specific to mycobacteria. Furtherteins, Immunity and Immunopathology blocked the T-cell recognition of more, precursor frequency, analysis was held in Utrecht on 2 April 1990. cytochrome c. The hsp was localized showed that hsp65 was not the 228 © 1990, Elsevier Science PublishErs Ltd, UK. 0 i 67-4919/90/502.00
Immunology Today, Vol. 1I, No. 7 1990
dominant antigen recognized by ~/~ T cells. ~/~ T-cell ligands probably include low molecular weight nonprotein antigens such as lipids and/or sugars (S. Kauffman)
specific response in JRA appears to be directed towards non-conserved regions of the hsp since the nonapeptide is not contained within the mammalian sequence (Y. Naparstek, Jerusalem). Role of immunity to hsp in arthritis Analysis of the specificity of mTcoAdjuvant arthritis can be induced bacterial hsp65-induced (SF) clones using M. tuberculosis in oil in Lewis from a self-limiting B27-/Dr4-ve reacrats and, to a lesser extent, in Fisher tive arthritis showed that they were and BN rats. Earlier studies had all directed to non-conserved aminoshown that the disease could be terminal peptides of the anti:~en (H. induced by the A2b T-cell clone Gaston, Birmingham). Studies on which recognizes Lhe nonapeptide T-cell clones from Yersinia arthritis, comprising residues 180-188 of showed thai 1 in 120 rea~ed with a mycobacterial hsp65. Induction of shared (conserved) epitope, common artnritis in the Lewio rat is associated to human and mycobacterial hsp65 with T-cell reactivity to this nonapep- (E. Hermann, Mainz). Short-term T-cell lines, from SF of tide. Both ~isher and BN rats fail to develop such a response (C. Boog, three RA patients showed elevated Utrecht). In experiments using a simi- ~,5 T-cell levels, compared with blood lar model where the arthritogen is T cells, in response to the mycobacstreptococcal cell walls (SCW), T-cell terial hsp65. Interestingly, many of reactivity to both SCW fragments and these -~ T cells were CD8 ÷ and were mycobacteria165 kDa hsp was absent n~ainly of the subset infrequently and no arthritis developed in Fisher found in the blood (R. Kiessling, rats. The fact that germ-free Fisher Stockholm). In contrast, other studies rats can be induced to develop have shown th3t RA ~/~T cells are not chronic arthritis and specific T-cell re- ~levated in the SF and sy,noyial memactivity argues for a role of the intes- brane (SM) and that the ~/6 T cells are tinal flora in maintenance of the re- found as sinq[e cells in the SM (F. fractory state to bozh SCW fragments Emmrich, Erlangen; P.M. Lydyard, and hsp65 in conventionally reared London). Furthermore, -~6 T cells Fisher rats (W.B. van den Berg, alone are not sufficient to induce AA in the rat (F. Emmrich). N~megen). This refractory state can be 'artificioily: induced in the Lewis rat AA Locaiization of hsp within the synoviai model by prior treatment with sol- joint Since the target antigen of effector ui~le mycobacterial hsp65, which also downregulates response to the nona- cells and antibodies could be the corn peptide (C. Boog); this treatment s~.n,~d region of hsp in arthritis, it also prevents SCW-induced arthritis i~ important to identify hsp within ~'~' ~ van uc,, "J^~ Berg) and partially in- the damaged joint. ML30 antibodies ~vv.~. hibits collagen-induced arthritis(L. stained the cytoplasm of the synovial KIareskog, Uppsala).The induced un- lining layer (E.R. de Graeff Meeder, responsiveness to the arthritogenic Utrecht) and, more intensely, the regimens istransferableby T ceilsand pannus-cartilage junction of synovial has both specific and nonspecific joints from AA rats (L. Klareskog). The significance of this, predominantly components in the case of the S C W model (W.B. van den Berg). Murine macrophage, staining is unclea, since pristane-induced arthriti~ (but not it is not the mitochondrial pattern agalactosyl IgG) was inhibitedby my- one might expect. Similar obsercoL.,cterial hsp65 but not by the vations were made in joints of E. coil GRoEL homologue, indicating collagen-induced arthritic rats. ML30 was also localized within some specificityof unresponsiveness synovial lining cells in the synovial (G.W. Rook, London). In human arthritis,T-cellresponses joints of RA and JRA patients (E.R. de to the mycobacterial hsp65 are eI~v- Graeff Meeder). The same antibody ated in rheumatoid arthritis(RA) syn- recognized a 65 kDa antigen on the ovialfluid(SF),compared with blood. surface of synovial macrophages in This was alsoshown forjuvenilerheu- RA synovial tissue (L. Klareskog). Inmatoid arthritis(JRA)and a few of the terestingly, a similar cytoplasmic dispatients also showing elevated anti- tribution in RA synoviai tissue was body responses to the hsp65 re- seen with an antibody to the 10 kDa sponded to the nonapeptide (M. hsp - a dominant antigen of M. tuDanieli,Ancona). Thus, much of the berculosis (A.R.M. Coates, London).
Role of immunityto hsp in dia~tes Recent studies with the non-obese diabetic (NOD) mouse have implicated hsp65 in the development of spontaneous diabetes (I. Cohen, Rehovot). Serum antibodies to hsp65 initially i.qcrease but have subsided before insulin-dependent diabetes mellitus (IDDM) becomes clinically apparent. The bulk of the T-cell response is directed towards human and murine forms of hsp65 and not hsp70. Immunization of pre-diabetic mice with hsp65 but not hsp70 induces an early self-limiting insulitis which prevents the mice from developing spontaneous disease. Prediabetic NOD mice can be induced to develop earlier disease fo'lowing injection of a T-cell clone directed to a 24 amino acid sequence of the human homologue. On the other hand, adndnistration of the peptide itself prevents development of spontaneous disease. As shown in the AA rat model, giving the T-cell clone in a cross-linked form (T-cell vacci~,ation) prevents spontaneous disease and stimulates host T-cell responses against the injected T-cell clones. Thus an anti-idiotypidc!onotypic response was seen ir the AA rat model and the murine '~DM model. A model by Cohen and Young attempted to explain this data - the apparent paradox that human T cells with specificity for conserved epitopes are present in normal individuals and the dominance of the hsp as microbial antigens. Lymphocytes forming a natural network carry receptors dire~ed towards a limited set of dominant ,,elf antigens, for example hsps. In this model, B cells would focus and internalize these self proteins (by binding to their conserved regions) for processing. These proteins would contain non-conserved sequences available to trigger non-seif reactive T cells and provide protection. Thus development of arthritis and diabetic autoim.muni~ could be the result of a defective regulation of this natural network. The possibilit7 of modulating ti~is network by vaccination with hsp pepficies and T--cell clones is an exciting prospect for the future. PeterM. Lydyardis.:~the Deptof lrnmunology, University College a,~d Middlesex School of Medione, London, UKand Willemvan Edenis at tke Dept of InfectiousDiseasesand Immunology, Facultyof VeterinaryMedicine,Utrecht Universlt),, The Netherlands.
229
#nmunology Today, Vol. 11, No 7 1990
Sandoz Prize: T-B collaboration
JacquesMiller The inaugura!SandozPrizeforlmmunology has been awarded to Drs Max Cooper of the University of Alabama, Birmingham, and Jacques Miller of the Walter and Eliza Hall Institute in Melbourne. The prize, presented at the AAI meeting in New Orleans in June, recognizes the contributions
competence, seminal work on T-B cell cooperation and insights into the function of CD4 and CD8 in T-cell activation. Max Cooper and colleagues were the first to establish that the immune system can be divided, developmentally and functionally, into B- and T-cell populations. He has contributed substantially to the understanding of B-cell ontogeny, the mechanismsand treatments of B-cell immunodeficiencies and the processes governing the development of B-cell neoplasms. The prize of $100 000 will henceforth be awarded biennially, with the winners selected by a prestigious international jury. The aim of the MaxCooper prize is both to honour achievement in immunology and to encourage of the winners to the elucidation further research. The latter is reof B-cell (Coopar) and T-cell (Miller) flected in the use of the winnings: biology. Jacques and Max will use 80% to Each has exerted a great influence fund further research. on his chosen field. Jacques Miller's achievements include the origina! Richard Gallagher demonstration of the ~-oleof the ti~ymus in the development of immunoEditorof ImmunologyToday.
Heat shock proteins: immunity and immunopathology ......
to endosomal and surface membranes of macrophages and B cells, but was not found on T and natural killer (NK) cells. A fundamental role for this particular hsp70 could be to prevent total degradation of the pepfrom PeterM. Lydyardand Willem van Eden tide within endosomes and to carry the peptides to the surface for coassembly with class II (and class I?) Much interest has been generated in heat viewed by D. Young, London). Pro- MHC molecules. shock proteins (hsps)since they were im- karyotic hsps of these families share plicated as dominant antigens of infec- as much as 60% homology with Immunityto heat shockproteins During infection, hsps are induced tious microorganisms and suggested to mammalian forms at the amino acid have a role in the development of adju- level. They occur constitutively but in both microorganisms and host vant arthntis (AA) in rats. Advancesin the can also be induced by a variety of phagocytes. The dominant antigens understanding of the role of hsps in im- stress conditions. !hey function as of intracellular microorganisms are 'molecular chaperones' (J. Ellis, Warmunity and immunopathology were re- wick) which are defined as proteins hsp65 and hsp70. Cloned 'autoreactive' T cells have been obtained from cently discussed at a meeting held in that mediate corrc.ct folding of other normal donors for human hsp65 and Utrecht*, as part of the European Com- proteins and, in so.me cases, their hsp70 (D. Young). Could such T cells munity concertedaction on immunopatho- assembly into oligomeric structures. damage 'stressed' cells? In fact, virally genesis and irnmunotherapy of chronic A constitutive member of the infected, gamma-interferon (IFN-~/)-or art,hritis. hsp70 family is involved in anti- heat-treated macrophages were killed gen processing and presentation by T cells from M. leprae infected Heat shock proteins can be divided (S. Pierce, Evanstown). Using anti- mice recognizing conserved epitopes into four major families, with mem- immunoglobulin covalently coupled of hsp65 (S. Kauffman, Ulm). bers of molecular mass of about to cytochrome c and murine B cells Previous studies have suggested a 90kDa, 70kDa, 60kDa and 10- as antigen-processing cells, it was role for ~/~ T cells in mycobacterial 30 kDa. Most of the discussionat the shown that small peptides of the anti- disease. In vitro stimulation of blood T meeting revolved around the 60 kDa gen can be detected intracellularly cells with M. tuberculosis extract inand 70 kDa family members (re- attached to a 72-74 kDa peptide- creased ~/a T cell numbers (S. Kauffbinding protein within minutes. man). However, this effect was not *The mini-symposiumon HeatShockPro- Antibodies to this 72-74 kDa hsp specific to mycobacteria. Furtherteins, Immunity and Immunopathology blocked the T-cell recognition of more, precursor frequency, analysis was held in Utrecht on 2 April 1990. cytochrome c. The hsp was localized showed that hsp65 was not the 228 © 1990, Elsevier Science PublishErs Ltd, UK. 0 i 67-4919/90/502.00
Immunology Today, Vol. 1I, No. 7 1990
dominant antigen recognized by ~/~ T cells. ~/~ T-cell ligands probably include low molecular weight nonprotein antigens such as lipids and/or sugars (S. Kauffman)
specific response in JRA appears to be directed towards non-conserved regions of the hsp since the nonapeptide is not contained within the mammalian sequence (Y. Naparstek, Jerusalem). Role of immunity to hsp in arthritis Analysis of the specificity of mTcoAdjuvant arthritis can be induced bacterial hsp65-induced (SF) clones using M. tuberculosis in oil in Lewis from a self-limiting B27-/Dr4-ve reacrats and, to a lesser extent, in Fisher tive arthritis showed that they were and BN rats. Earlier studies had all directed to non-conserved aminoshown that the disease could be terminal peptides of the anti:~en (H. induced by the A2b T-cell clone Gaston, Birmingham). Studies on which recognizes Lhe nonapeptide T-cell clones from Yersinia arthritis, comprising residues 180-188 of showed thai 1 in 120 rea~ed with a mycobacterial hsp65. Induction of shared (conserved) epitope, common artnritis in the Lewio rat is associated to human and mycobacterial hsp65 with T-cell reactivity to this nonapep- (E. Hermann, Mainz). Short-term T-cell lines, from SF of tide. Both ~isher and BN rats fail to develop such a response (C. Boog, three RA patients showed elevated Utrecht). In experiments using a simi- ~,5 T-cell levels, compared with blood lar model where the arthritogen is T cells, in response to the mycobacstreptococcal cell walls (SCW), T-cell terial hsp65. Interestingly, many of reactivity to both SCW fragments and these -~ T cells were CD8 ÷ and were mycobacteria165 kDa hsp was absent n~ainly of the subset infrequently and no arthritis developed in Fisher found in the blood (R. Kiessling, rats. The fact that germ-free Fisher Stockholm). In contrast, other studies rats can be induced to develop have shown th3t RA ~/~T cells are not chronic arthritis and specific T-cell re- ~levated in the SF and sy,noyial memactivity argues for a role of the intes- brane (SM) and that the ~/6 T cells are tinal flora in maintenance of the re- found as sinq[e cells in the SM (F. fractory state to bozh SCW fragments Emmrich, Erlangen; P.M. Lydyard, and hsp65 in conventionally reared London). Furthermore, -~6 T cells Fisher rats (W.B. van den Berg, alone are not sufficient to induce AA in the rat (F. Emmrich). N~megen). This refractory state can be 'artificioily: induced in the Lewis rat AA Locaiization of hsp within the synoviai model by prior treatment with sol- joint Since the target antigen of effector ui~le mycobacterial hsp65, which also downregulates response to the nona- cells and antibodies could be the corn peptide (C. Boog); this treatment s~.n,~d region of hsp in arthritis, it also prevents SCW-induced arthritis i~ important to identify hsp within ~'~' ~ van uc,, "J^~ Berg) and partially in- the damaged joint. ML30 antibodies ~vv.~. hibits collagen-induced arthritis(L. stained the cytoplasm of the synovial KIareskog, Uppsala).The induced un- lining layer (E.R. de Graeff Meeder, responsiveness to the arthritogenic Utrecht) and, more intensely, the regimens istransferableby T ceilsand pannus-cartilage junction of synovial has both specific and nonspecific joints from AA rats (L. Klareskog). The significance of this, predominantly components in the case of the S C W model (W.B. van den Berg). Murine macrophage, staining is unclea, since pristane-induced arthriti~ (but not it is not the mitochondrial pattern agalactosyl IgG) was inhibitedby my- one might expect. Similar obsercoL.,cterial hsp65 but not by the vations were made in joints of E. coil GRoEL homologue, indicating collagen-induced arthritic rats. ML30 was also localized within some specificityof unresponsiveness synovial lining cells in the synovial (G.W. Rook, London). In human arthritis,T-cellresponses joints of RA and JRA patients (E.R. de to the mycobacterial hsp65 are eI~v- Graeff Meeder). The same antibody ated in rheumatoid arthritis(RA) syn- recognized a 65 kDa antigen on the ovialfluid(SF),compared with blood. surface of synovial macrophages in This was alsoshown forjuvenilerheu- RA synovial tissue (L. Klareskog). Inmatoid arthritis(JRA)and a few of the terestingly, a similar cytoplasmic dispatients also showing elevated anti- tribution in RA synoviai tissue was body responses to the hsp65 re- seen with an antibody to the 10 kDa sponded to the nonapeptide (M. hsp - a dominant antigen of M. tuDanieli,Ancona). Thus, much of the berculosis (A.R.M. Coates, London).
Role of immunityto hsp in dia~tes Recent studies with the non-obese diabetic (NOD) mouse have implicated hsp65 in the development of spontaneous diabetes (I. Cohen, Rehovot). Serum antibodies to hsp65 initially i.qcrease but have subsided before insulin-dependent diabetes mellitus (IDDM) becomes clinically apparent. The bulk of the T-cell response is directed towards human and murine forms of hsp65 and not hsp70. Immunization of pre-diabetic mice with hsp65 but not hsp70 induces an early self-limiting insulitis which prevents the mice from developing spontaneous disease. Prediabetic NOD mice can be induced to develop earlier disease fo'lowing injection of a T-cell clone directed to a 24 amino acid sequence of the human homologue. On the other hand, adndnistration of the peptide itself prevents development of spontaneous disease. As shown in the AA rat model, giving the T-cell clone in a cross-linked form (T-cell vacci~,ation) prevents spontaneous disease and stimulates host T-cell responses against the injected T-cell clones. Thus an anti-idiotypidc!onotypic response was seen ir the AA rat model and the murine '~DM model. A model by Cohen and Young attempted to explain this data - the apparent paradox that human T cells with specificity for conserved epitopes are present in normal individuals and the dominance of the hsp as microbial antigens. Lymphocytes forming a natural network carry receptors dire~ed towards a limited set of dominant ,,elf antigens, for example hsps. In this model, B cells would focus and internalize these self proteins (by binding to their conserved regions) for processing. These proteins would contain non-conserved sequences available to trigger non-seif reactive T cells and provide protection. Thus development of arthritis and diabetic autoim.muni~ could be the result of a defective regulation of this natural network. The possibilit7 of modulating ti~is network by vaccination with hsp pepficies and T--cell clones is an exciting prospect for the future. PeterM. Lydyardis.:~the Deptof lrnmunology, University College a,~d Middlesex School of Medione, London, UKand Willemvan Edenis at tke Dept of InfectiousDiseasesand Immunology, Facultyof VeterinaryMedicine,Utrecht Universlt),, The Netherlands.
229
