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Antigen-based immunointervention in autoimmune diseases
very early in two of the three patients studied, there was no evidence of selective pressure exerted by the humoral HIV-specific immune response. All together, these results indicated that the virus-specific immune response, and in partitular the cell-mediated immune response, significantly influences the evolution of HIV How-
Antigen-based
ever, a number of mechanisms such as emergence of virus mutants resistant to the immune response, clonal deletion of HIV-specific cytotoxic T cells and accumulation of cytotoxic T cells in peripheral blood operate very early during primary infection, and promote virus escape from the immune response.
~mmunointervention Chairperson : L. Adorini
The dominant theme of the session revolved around the effect of antigen administration on the induction of peripheral tolerance and on the regulation of Thf and Th2 cells in autoi~~e disease models. The Thl/ThZ paradigm of immunoregulation is obviously an oversimplification of the intricacies of the immune system, but it offers useful reference points. The concept of immune deviation was explored in detail and several novel facets emerged. L. Adorini (Milano) demonstrated that immune deviation to Th2 by administration of the natural IL12 antagonist p40 homodimer to NOR mice is associated with inhibition of the Thl response to ID~M-associated self antigens and to prevention of diabetes. However, treatment initiated after the onset of insulitis, when Thl cells have already infiltrated the pancreatic islets, is much less effective. This is consistent with the observation that polarized TCR transgenic Thl cells do not reverse their phenotype when restimulated by antigen in the presence of p40 homodimer, although their further recruitment is prevented. Therefore, protection from IDDM appears to be associated with immune deviation to the Th2 phenoty~. E. Sercarz (Los Angeles) described the opposing consequences of immune deviation in a regu-
in autoimmune
diseases
(Milan)
latory circuit spontaneously recruited to downregulate encephalitogenic MBP-specific effector CD4+ cells, which use predo~n~tly Vp8.2. The circuit is composed of at least two subsets, one CD4+ (Treg) and the other CD8+ (Tsup). Tregs are specific for the determinant 76-101 of Vp8.2 molecules and their removal leads to prolongation and relapses of EAE. Tsups also recognize a determinant on Vp8.2, which is restricted by class I molecules and different from the previous one. Intriguingly, Tregs appear to need a Thltype environment to effectively recruit CD8+ Tsups and thus downregulate pathogenic Thl effecters. Together, these two cell types can protect from EAE. However, when peptide 76-101 is used to induce immune deviation towards Th2 in the absence of a Thl-favouring milieu, enhanced EAE is induced. This clearly shows how the ThllTh2 paradigm can be more complex than expected, or hoped for. Antigen-based immunointervention in the treatment of MS was illustrated by D. Hafler (Boston). The encephalitogenic PLP peptide 139151 induces Thl cells, whereas immunization with a single residue-substi~ted peptide induces Th2 and ThO-type cells. The altered peptide can induce EAE reversal when administered at the
420
SUMMARY OF SESSIONS
first symptoms of EAE, and it is able to induce bystander suppression of the response to other encephalitogenic antigens. If bystander suppression can be exploited clinically, it could greatly facilitate the development of antigen-based immunotherapy. Similarly, the APL MBP8599(93A) could alter the cytokine profile of autoreactive human T-cell clones specific for the wild-type 8599 sequence, switching them from a ThO to a Th2 phenotype. However, the effects of APL are unpredictable and the same APL could induce, according to the TCR of the clone, predominant IFNy or IL4 secretion. The clinical relevance of these findings should soon become apparent, as MBP85-99(93A) is currently under evaluation in MS patients. APL were also described by W. van Eden (Utrecht), who showed that nasal instillation of hsp179-190( 183A), an APL corresponding to a mycobacterial hsp60 determinant possibly mimicking an as yet undefined cartilage-associated epitope, could inhibit adjuvant and avridine (nonmycobacterial)-induced arthritis by 60 %. Mucosal tolerance was discussed in detail by D. Wraith (Bristol) in the EAE model. After intranasal instillation of MBPl-9 to primed mice, all cytokines tested were inhibited, except ILIO, which was secreted in the range of 10 rig/ml, possibly sufficient to explain the beneficial effect of intranasal antigen administration on EAE. Immunoregulation in mouse collagen-induced arthritis (CIA), a model for human RA, was discussed by
H. Hess (Milan). He stressed the differential effects IL12 can have in the pathogenesis of CIA. In susceptible mice under poorly arthritogenic stimulation, exogenous IL12 profoundly enhanced cellular and humoral anti-collagen type II (CII) responses and triggered arthritis. Conversely, using optimal arthritogenic conditions, high doses of IL12 were able to markedly ameliorate joint disease without inhibiting the Thl response. The opposing effects of the classical Thl-promoting cytokine, in this case dependent on its dosage and adjuvant, might be another hint to discrete subsets within Thl cells. Antigen-based immunointervention requires the identification of MHC-binding sequences within protein antigens, and ultimately the ability to predict them. A binding motif for I-Aa7, the MHC class II molecule expressed by APC from NOD and Biozzi AB/I-I mice, was described (S. Gregori, Milan). This should help in the identification of potential T-cell epitopcs of self and foreign origin involved in the pathogenesis, and in principle, applicable to the immunotherapy, of IDDM and CR-EAE, respectively. However, precise identification of the inciting autoantigen may not be an absolute prerequisite for antigen-based immunointervention. Administration of any self antigen able to induce a strong Th2 response in the target organ should be able to inhibit pathogenic Thl cells. It will be interesting to see whether this concept may be transferred into clinical practice.
T-cell tolerance Chairperson
: A. Kruisbeek
Introduction T-cell tolerance can be achieved through many different mechanisms, in both the thymus and the periphery. From the perspective that successful
(Amsterdam)
manipulation of the immune system requires a better understanding of the mechanisms underlying immunological tolerance, this topic has received extensive attention over the past few years. Considerable work has highlighted how
Antigen-based
ever, a number of mechanisms such as emergence of virus mutants resistant to the immune response, clonal deletion of HIV-specific cytotoxic T cells and accumulation of cytotoxic T cells in peripheral blood operate very early during primary infection, and promote virus escape from the immune response.
~mmunointervention Chairperson : L. Adorini
The dominant theme of the session revolved around the effect of antigen administration on the induction of peripheral tolerance and on the regulation of Thf and Th2 cells in autoi~~e disease models. The Thl/ThZ paradigm of immunoregulation is obviously an oversimplification of the intricacies of the immune system, but it offers useful reference points. The concept of immune deviation was explored in detail and several novel facets emerged. L. Adorini (Milano) demonstrated that immune deviation to Th2 by administration of the natural IL12 antagonist p40 homodimer to NOR mice is associated with inhibition of the Thl response to ID~M-associated self antigens and to prevention of diabetes. However, treatment initiated after the onset of insulitis, when Thl cells have already infiltrated the pancreatic islets, is much less effective. This is consistent with the observation that polarized TCR transgenic Thl cells do not reverse their phenotype when restimulated by antigen in the presence of p40 homodimer, although their further recruitment is prevented. Therefore, protection from IDDM appears to be associated with immune deviation to the Th2 phenoty~. E. Sercarz (Los Angeles) described the opposing consequences of immune deviation in a regu-
in autoimmune
diseases
(Milan)
latory circuit spontaneously recruited to downregulate encephalitogenic MBP-specific effector CD4+ cells, which use predo~n~tly Vp8.2. The circuit is composed of at least two subsets, one CD4+ (Treg) and the other CD8+ (Tsup). Tregs are specific for the determinant 76-101 of Vp8.2 molecules and their removal leads to prolongation and relapses of EAE. Tsups also recognize a determinant on Vp8.2, which is restricted by class I molecules and different from the previous one. Intriguingly, Tregs appear to need a Thltype environment to effectively recruit CD8+ Tsups and thus downregulate pathogenic Thl effecters. Together, these two cell types can protect from EAE. However, when peptide 76-101 is used to induce immune deviation towards Th2 in the absence of a Thl-favouring milieu, enhanced EAE is induced. This clearly shows how the ThllTh2 paradigm can be more complex than expected, or hoped for. Antigen-based immunointervention in the treatment of MS was illustrated by D. Hafler (Boston). The encephalitogenic PLP peptide 139151 induces Thl cells, whereas immunization with a single residue-substi~ted peptide induces Th2 and ThO-type cells. The altered peptide can induce EAE reversal when administered at the
420
SUMMARY OF SESSIONS
first symptoms of EAE, and it is able to induce bystander suppression of the response to other encephalitogenic antigens. If bystander suppression can be exploited clinically, it could greatly facilitate the development of antigen-based immunotherapy. Similarly, the APL MBP8599(93A) could alter the cytokine profile of autoreactive human T-cell clones specific for the wild-type 8599 sequence, switching them from a ThO to a Th2 phenotype. However, the effects of APL are unpredictable and the same APL could induce, according to the TCR of the clone, predominant IFNy or IL4 secretion. The clinical relevance of these findings should soon become apparent, as MBP85-99(93A) is currently under evaluation in MS patients. APL were also described by W. van Eden (Utrecht), who showed that nasal instillation of hsp179-190( 183A), an APL corresponding to a mycobacterial hsp60 determinant possibly mimicking an as yet undefined cartilage-associated epitope, could inhibit adjuvant and avridine (nonmycobacterial)-induced arthritis by 60 %. Mucosal tolerance was discussed in detail by D. Wraith (Bristol) in the EAE model. After intranasal instillation of MBPl-9 to primed mice, all cytokines tested were inhibited, except ILIO, which was secreted in the range of 10 rig/ml, possibly sufficient to explain the beneficial effect of intranasal antigen administration on EAE. Immunoregulation in mouse collagen-induced arthritis (CIA), a model for human RA, was discussed by
H. Hess (Milan). He stressed the differential effects IL12 can have in the pathogenesis of CIA. In susceptible mice under poorly arthritogenic stimulation, exogenous IL12 profoundly enhanced cellular and humoral anti-collagen type II (CII) responses and triggered arthritis. Conversely, using optimal arthritogenic conditions, high doses of IL12 were able to markedly ameliorate joint disease without inhibiting the Thl response. The opposing effects of the classical Thl-promoting cytokine, in this case dependent on its dosage and adjuvant, might be another hint to discrete subsets within Thl cells. Antigen-based immunointervention requires the identification of MHC-binding sequences within protein antigens, and ultimately the ability to predict them. A binding motif for I-Aa7, the MHC class II molecule expressed by APC from NOD and Biozzi AB/I-I mice, was described (S. Gregori, Milan). This should help in the identification of potential T-cell epitopcs of self and foreign origin involved in the pathogenesis, and in principle, applicable to the immunotherapy, of IDDM and CR-EAE, respectively. However, precise identification of the inciting autoantigen may not be an absolute prerequisite for antigen-based immunointervention. Administration of any self antigen able to induce a strong Th2 response in the target organ should be able to inhibit pathogenic Thl cells. It will be interesting to see whether this concept may be transferred into clinical practice.
T-cell tolerance Chairperson
: A. Kruisbeek
Introduction T-cell tolerance can be achieved through many different mechanisms, in both the thymus and the periphery. From the perspective that successful
(Amsterdam)
manipulation of the immune system requires a better understanding of the mechanisms underlying immunological tolerance, this topic has received extensive attention over the past few years. Considerable work has highlighted how