The GP120 molecule of HIV-1 and its interaction with T cells.

The gp120 molecule of HIV-1 is a glycoprotein that is part of the outer layer of the virus. It presents itself as viral membrane spikes consisting of 3 molecules of gp120 linked together and anchored to the membrane by gp41 protein. Gp120 is essential for viral infection as it facilitates HIV entry into the host cell and this is its best-known and most researched role in HIV infection. However, it is becoming increasingly evident that gp120 might also be facilitating viral persistence and continuing HIV infection by influencing the T cell immune response to the virus. Several mechanisms might be involved in this process of which gp120 binding to the CD4 receptor of T cells is the best known and most important interaction as it facilitates viral entry into the CD4+ cells and their depletion, a hallmark of the HIV infection. Gp120 is shed from the viral membrane and accumulates in lymphoid tissues in significant amounts. Here, it can induce apoptosis and severely alter the immune response to the virus by dampening the antiviral CTL response thus impeding the clearance of HIV. The effects of gp120 and how it interacts and influences T cell immune response to the virus is an important topic and this review aims to summarize what has been published so far in hopes of providing guidance for future work in this area.

Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just "witnesses of disease"?

Pemphigus vulgaris (PV) is fascinating to dermatologists, epithelial biologists and immunologists alike, as its pathogenesis has been clarified to a much greater extent than that of most other organ-specific autoimmune diseases, and as it has provided abundant novel insights into desmoglein biology and pathology along the way. Historically, the most influential PV pathogenesis concept is that of Stanley and Amagai. This concept holds that autoantibodies against desmogleins are both essential and sufficient for epidermal blister formation (acantholysis) by impeding the normal functioning of these major adhesion proteins. However, as with most good theories, this landmark concept has left a number of intriguing and important questions open (or at least has not managed to answer these to everyone's satisfaction). Moreover, selected dissenting voices in the literature have increasingly called attention to what may or may not be construed as inconsistencies in this dominant PV pathogenesis paradigm of the recent past. The present debate feature therefore bravely rises to the challenge of re-examining the entire currently available evidence, as rationally and as undogmatically as possible, by provocatively asking a carefully selected congregation of experts (who have never before jointly published on this controversial topic!) to discuss how essential anti-desmoglein autoantibodies really are in the immunopathogenesis of PV. Not surprisingly, some of our expert "witnesses" in this animated debate propose diametrically opposed answers to this question. While doing so, incisive additional questions are raised that relate to the central one posed, and our attention is called to facts that may deserve more careful consideration than they have received so far. Together with the intriguing (often still very speculative) complementary or alternative pathogenesis scenarios proposed in the following pages, this offers welcome "food for thought" as well as very specific suggestions for important future research directions--within and beyond the camp of PV aficionados. The editors trust that this attempt at a rational public debate of the full evidence that is currently at hand will constructively contribute to further dissecting the exciting--and clinically very relevant!--immunopathogenesis of PV in all its complexity.

Allele frequencies for 15 autosomal STR loci and admixture estimates in Puerto Rican Americans.

Allelic frequencies of 15 short tandem repeats (STR) markers (CSF1PO, FGA, THO1, TPOX, VWA, D3S11358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, D19S433 and D2S1338) were determined using the AmpFl STR Identifiler PCR Amplification Kit in Puerto Rican American individuals (N=205) from Massachusetts. The FGA, D18S51 and D2S1338 loci had a high power of discrimination (PD) with values of 0.967, 0.965 and 0.961, respectively. Significant deviations from the Hardy-Weinberg (HW) equilibrium were not detected. An important genetic contribution of Caucasian European (76.4%) was detected in Puerto Rican Americans. However, comparative analysis between Puerto Rican American and other neighboring populations from United States mainly with African and Caucasian Americans, revealed significant differences in the distribution of STR markers. Our results are important for future comparative genetic studies of different American ethnic groups, in particular a cultural group called Hispanic-Americans and should be helpful for forensic and paternity testing.

Synthetic peptides that inhibit binding of the myelin basic protein 85-99 epitope to multiple sclerosis-associated HLA-DR2 molecules and MBP-specific T-cell responses.

Copolymer 1 (Cop 1, poly [Y, E, A, K]) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS), a disease that is linked to HLA-DR2 (DRB1*1501). In the present study various peptides, synthesized according to the binding motifs for both the immunodominant epitope of myelin basic protein (MBP) 85-99, a candidate autoantigen in MS, and Cop 1, differentially inhibited binding of these antigens to disease-associated HLA-DR2 (DRB1*1501) molecules. In particular, two peptides with residue K at position P-1, as referred to MBP 85-99, inhibited effectively the binding of both biotinylated MBP 85-99 and Cop 1 to HLA-DR2 molecules as well as IL-2 production by two MBP-specific HLA-DR2-restricted T-cell clones. These findings suggest the possible utility of these compounds or their more stable derivatives in treatment of MS.

Synthetic peptides that inhibit binding of the collagen type II 261-273 epitope to rheumatoid arthritis-associated HLA-DR1 and -DR4 molecules and collagen-specific T-cell responses.

Copolymer 1 [Cop 1, poly (Y, E, A, K)] is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS), a disease that is linked to HLA-DR2 (DRB1*1501). Another copolymer [poly (Y, A, K)] was also identified that binds to rheumatoid arthritis (RA)-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules and inhibits the response of HLA-DR1- and -DR4-restricted T cell clones to an immunodominant epitope of collagen type II (CII) 261-273 (a candidate autoantigen in RA). In the present study various peptides have been synthesized based on binding "motifs" of Cop 1 for HLA-DR1 and -DR4 molecules. Those peptides with K at P-1 or K at P8 were particularly effective as inhibitors of binding of CII 261-273, of Cop 1 and of the influenza virus hemagglutinin peptide 306-318 to these class II proteins. Moreover, several of them were also potent inhibitors of the CII 261-273-reactive T cell clones. These findings suggest that small peptides or their more stable derivatives may be able to substitute for copolymers in the treatment of RA, and by implication of MS.

Binding of random copolymers of three amino acids to class II MHC molecules.

Copolymer 1 [Cop 1, poly(Y,E,A,K)] is a random synthetic amino acid copolymer of L-tyrosine, L-glutamic acid, L-alanine and L-lysine, effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to purified human HLA-DR molecules within the peptide-binding groove. In the present study the binding of copolymers composed of three of the four amino acids found in poly(Y,E,A,K) to purified class II MHC molecules was examined. Poly(Y,A,K) and poly(Y,E,A,K) bound to purified human HLA-DR1 or -DR4 molecules with affinity higher than poly(Y,E,A), poly(E,A,K) or poly(Y,E,K), whereas poly(Y,E,A,K) and poly(E,A,K) were the better binders of HLA-DR2 molecules. On the other hand, poly(Y,E,A) and poly(Y,A,K) inhibited the binding of biotinylated poly(Y,E,A,K) to these molecules 10-fold more efficiently than poly(Y,E,K). Finally, poly(Y,E,A), poly(Y,A,K) and poly(E,A,K) were cross-reactive with poly(Y,E,A,K) using YEAK-specific T cell lines and clones of mouse or human origin.

Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated HLA-DR molecules.

Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis.

Synthetic amino acid copolymers that bind to HLA-DR proteins and inhibit type II collagen-reactive T cell clones.

Copolymer 1 [poly(Y,E,A,K)] is a random synthetic amino acid copolymer of L-tyrosine, L-glutamic acid, L-alanine, and L-lysine that is effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Copolymer 1 binds promiscuously and very efficiently to purified HLA-DR molecules within the peptide-binding groove. In the present study, YEAK and YEAK-related copolymers and type II collagen (CII) peptide 261-273, a candidate autoantigen in rheumatoid arthritis (RA), competed for binding to RA-associated HLA-DR molecules encoded by DRB1*0101 and DRB1*0401. Moreover, these copolymers (particularly YEAK, YAK, and YEK) inhibited the response of DR1- and DR4-restricted T cell clones to the CII epitope 261-273 by >50%. This direct evidence both for competitive interactions of these copolymers and CII peptide with RA-associated HLA-DR molecules and for inhibition of CII-specific T cell responses suggests that these compounds should be evaluated in animal models for rheumatoid arthritis.

Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules.

Copolymer 1 (Cop 1) is a random synthetic amino acid copolymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to living APCs of various HLA haplotypes. In the present study, a substantial part of the whole mixture of random polypeptides that compose Cop 1 was shown to bind to purified human HLA-DR1, DR2, and DR4 with high affinity in a temperature- and time (and, in the case of DR4, pH)-dependent manner, and was competitively inhibited by DR-restricted peptides, but not by peptide derivatives that bind with low affinity. Bacterial superantigens inhibited Cop 1 binding only at very high concentrations. The formation of the Cop 1-DR1 complex was also shown by SDS-PAGE. These findings represent the first direct evidence for interactions of Cop 1 with purified DR molecules, and suggest that its effectiveness in experimental allergic encephalomyelitis and multiple sclerosis may be directly related to its binding in the groove of HLA-DR proteins.

Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells.

Copolymer 1 (Cop 1), a synthetic copolymer of amino acids, effective in suppression of experimental allergic encephalomyelitis (EAE) and myelin basic protein (MBP), was shown to bind extensively and promiscuously to the class II MHC molecules on antigen-presenting cells (APC) without prior processing. In the case of human APC, binding has earlier been demonstrated to DR but not DQ or class I molecules. In the present study, we examined whether binding of Cop 1 and MBP affects MHC class II expression on the cell membrane. Biotinylated derivatives of these antigens were used to monitor their direct binding to MHC molecules on living APC by flow cytometry using phycoerythrin-streptavidin, while the levels of MHC surface expression were monitored by staining with FITC-conjugated anti-class I- and class II-specific antibodies. When Cop 1 or MBP were incubated with the APC, intensity of cell staining with anti-DR, but not with anti-DQ or anti-class I antibodies, was significantly increased, compared to the staining of control APC not reacted with these antigens. In contrast, staining intensity was unaffected when p84-102, a human immunodominant epitope of MBP, or ovalbumin (OVA), a protein which undergoes proteolytic degradation prior to binding, were incubated with the APC. Cycloheximide, a protein synthesis inhibitor, had no effect on the enhanced staining intensity with anti-DR antibody of cells treated with Cop 1 or MBP, whereas it inhibited the enhanced staining of both DR and DQ molecules caused by the respective antibodies, in the absence of these antigens. Brefeldin A, a protein transport inhibitor, lowered the levels of staining intensity with anti-DR and anti-DQ antibodies in both cases, with and without antigen added to the APC. Fluorescence microscopic analysis revealed that cells incubated with Cop 1 or MBP, but not with p84-102 or OVA, exhibit both bright staining of the cell membrane and clusters produced by the aggregation of DR molecules with these antigens. Taken together, these observations indicate that Cop 1 and MBP, due to their polyvalent character, lead to increased fluorescence intensity of their complexes with HLA-DR, possibly due to recruitment and clustering of previously synthesized DR molecules. This can explain the efficient binding of these antigens to the MHC class II molecules.

The effect of linomide, an immunoregulator in experimental autoimmune diseases, on humoral antibody responses in mice.

Linomide (quinoline-3-carboxamide), a well tolerated, orally administered compound was recently shown to be effective in the prevention and treatment of several autoimmune diseases in experimental animal models. We have investigated its effect on specific humoral immune responses directed to T-cell-dependent soluble or particulate antigens and to a T cell-independent antigen in several mouse strains. Linomide administered after antigen priming did not affect primary and secondary antibody responses directed to T-cell particulate antigens (SRBC) or soluble antigens given with or without complete Freund's Adjuvant (CFA). Linomide treatment given prior to antigen priming did not affect the antibody response to a soluble antigen (TNP-KLH) given with an adjuvant. In contrast, dose-dependent down regulation of primary antibody responses was observed when T cell-dependent (BSA-dextran) or T-cell-independent (TNP-Ficoll) antigens were administered in an immunogenic form without adjuvant after starting Linomide treatment. The primary anti-SRBC antibody response was also suppressed by high dose Linomide given prior to immunization although normal secondary responses were retained. It is worth noting that no immunosuppressive effects on antibody responses were found at low dose ranges which effectively reversed T cell dependent autoimmune manifestation.

Regulatory feedback pathways in the thymus.

The idea that thymocytopoiesis may be subject to feedback regulation by mature lymphocytes is proposed on the basis of recent data from in vitro experimental models. Analysis of the data using mathematical models, presented here by Ramit Mehr and colleagues, suggests possible feedback control mechanisms in T-cell development.

Feedback regulation of T cell development: manifestations in aging.

Recent findings have indicated that mature T cells may regulate thymocytopoiesis in an age-related differential manner. The studies were based on T lymphocyte development in mouse fetal thymus stroma colonized with immature thymocytes and CD4+ T cells from young or old donors. In the present study, we used mathematical modeling and computer simulations in order to identify the thymocyte subsets that are targets for this type of regulation, and the processes affected by it. Our results suggest that thymocyte development is subject to regulation through 2 feedback loops: mature CD4+ cells exert a negative feedback on the double-negative to double-positive transition and on double-positive subset growth, and a positive feedback on the double-positive to CD4 single-positive transition. These effects may operate, in young mice, through a reduction in the rate of death of CD4+8- thymocytes, and a faster maturation of double-positive cells. In old mice, our simulations suggest that there may additionally be a reduction in double-positive proliferation rate. In some, but not all, of the simulations of old donor- derived thymocytes, we also had to assume a reduction in double-negative to double-positive differentiation, an increase in double-positive death rates, an increase of CD4+8- cell division rate, and a decrease of differentiation to the CD8 lineage.

Feedback regulation of T cell development in the thymus.

Recent findings suggest that mature T cells in the thymus may regulate the growth and differentiation of immature thymocytes. Here we use mathematical modeling and computer simulations to identify the thymocyte subsets that might serve as targets for regulation, and the processes that might be affected by regulation. Our results suggest that thymocyte development is subject to regulation through two feedback loops: mature CD4+ T cells exert a positive feedback on the single positive CD4+8- thymocyte compartment, by reducing CD4+8- cell death and possibly accelerating the differentiation of CD4+8+ thymocytes into CD4+8- thymocytes; they may also exert a negative feedback on the double-positive CD4+8+ thymocyte compartment, by reducing the proliferation or accelerating the maturation of these cells.

The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease.

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major malign proteins--myelin basic protein (MBP) and proteolipid protein (PLP)--have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer crossreactive with MBP and highly protective against the induction of EAE with MBP or PLP, is not being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity in MOG can also be pathogenic by inducing neurological disease in H-2u and H-2b mice with the same peptide of MOG, pMOG 35-55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.

Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses.

Copolymer 1 (Cop 1) is a synthetic amino acid copolymer effective in suppression of experimental allergic encephalomyelitis (EAE) and developed as a candidate drug for multiple sclerosis (MS). In the present study, we induced chronic relapsing (CR)-EAE in (SJL/J X BALB/c)F1 mice by either whole spinal cord homogenate or two synthetic peptides of proteolipid protein (PLP), p139-151 and p178-191. When Cop 1 was added to the encephalitogenic inoculum, mice were almost completely resistant to disease induction. T cell lines to p139-151 and p178-191 were specific to these peptides. Their antigen-specific responses were inhibited by Cop 1 in a dose-dependent manner, while their polyclonal response to the superantigen staphylococcal enterotoxin A (SEA) was not affected by Cop 1. Using biotinylated PLP derivatives, we demonstrated that the two PLP peptides bound to I-A(s) molecules, and that their binding was completely inhibited by unlabelled Cop 1. Furthermore, Cop 1 could displace the PLP peptides from the MHC binding site. These results support the potential of Cop 1 as a broad-spectrum drug for MS.

Lymphocyte development in irradiated thymuses: dynamics of colonization by progenitor cells and regeneration of resident cells.

Lymphocyte development in irradiated thymuses was analyzed using two complementary strategies: an in vitro experimental model and computer simulations. In the in vitro model, fetal thymus lobes were irradiated and the regeneration of cells that survived irradiation were examined, with the results compared to those of reconstitution of the thymus by donor bone marrow cells and their competition with the thymic resident cells. In vitro measurements of resident cell kinetics showed that cell proliferation is slowed down significantly after a relatively low (10 Gy) irradiation dose. Although the number of thymocytes that survived irradiation remained low for several days post-irradiation, further colonization by donor cells was not possible, unless performed within 6 h after irradiation. These experimental results, coupled with the analysis by computer simulations, suggest that bone marrow cell engraftment in the irradiated thymus may be limited by the presence of radiation-surviving thymic resident cells and the reduced availability of seeding niches.

Synthetic copolymer 1 and myelin basic protein do not require processing prior to binding to class II major histocompatibility complex molecules on living antigen-presenting cells.

In the present study we attempted to examine whether copolymer 1 (Cop 1), a synthetic basic random copolymer of amino acids (a candidate drug for multiple sclerosis (MS)), and myelin basic protein (MBP) undergo processing prior to their binding to MHC class II molecules on antigen-presenting cells (APC). The direct binding of biotinylated Cop 1 and MBP to living APC was monitored by flow cytometry using phycoerythrin (PE)-streptavidin. The time course for either Cop 1 or MBP binding was similar at 37 degrees C and on ice. Both Cop 1 and MBP bound to glutaraldehyde-fixed APC. Furthermore, these biotinylated antigens bound also in the presence of protease inhibitors and lysosomotropic agents, suggesting that proteolysis is not required prior to their interaction with the MHC determinants. Finally, short fragments of Cop 1 molecule did not bind to most of the APC, suggesting that the polymeric nature of Cop 1 is important for its efficient and promiscuous binding.

MHC-linked colonization of the thymus and thymocyte development: effects of mature T lymphocytes.

Effects of mature T lymphocytes on thymic colonization by lymphohemopoietic cells were investigated in an in vitro experimental model, using a variety of experimental strategies. Lymphoid-depleted fetal thymus (FT) explants (C57BL/Ka, Thy1.1, H-2b) were incubated with bone marrow (BM) cells from syngeneic (C57BL/Ka; SBM) and allogeneic (BALB/c, Thy1.2, H-2d; ABM) donors. Cocultures of FT with SBM and ABM, depleted of Thy1+ or of CD3+ cells, resulted in equal proportions of lymphocytes from both BM donors. When peripheral blood lymphocytes (PBL) from synegenic or semi-allogeneic donors (F1[C57BL/Ka x C57BL/6J], Thy1.1/Thy1.2); or F1[C57BL/Ka x BALB/c], Thy1.1/Thy1.2, respectively) were added to these cultures, the total lymphocyte count per thymic lobe decreased and a developmental preference of the SBM-derived cells, as compared to the ABM-derived cells, was noted. Cells of the PBL types were also observed in the cultures. Cocultures of FT with ABM and PBL showed reduced proportions of ABM-derived cells and occurrence of cells of the PBL type. Finally, FT explants partially depleted of lymphocytes by irradiation (6 Gy), were cocultured with PBL from either syngeneic or allogeneic donors. In the presence of syngeneic PBL, the total number of cells and the proportion of double-positive (CD4+CD8+) T cells were similar to those in the FT cultured by itself, whereas in the presence of allogeneic PBL these values were reduced. The study suggests that mature T lymphocytes may play a role in the developmental processes in the thymus, and points to MHC-linked selective effects.

Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity.

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and is being tested as a candidate drug for multiple sclerosis. It has been previously demonstrated that Cop 1 is immunologically cross-reactive with the autoantigen myelin basic protein (BP) and competitively inhibits the response to BP of T-cell lines and clones of different major histocompatibility complex (MHC) restrictions, of both mouse and human origin. In the present study we demonstrated the direct binding of Cop 1, using its biotinylated derivative, to MHC molecules on living antigen-presenting cells. Binding of biotinylated BP and peptide p84-102 (an immunodominant epitope of BP) was also demonstrated. Cop 1 and BP bound in a promiscuous manner to different types of antigen-presenting cells of various H-2 and HLA haplotypes. The specificity of the binding was confirmed by its inhibition with either the relevant anti-MHC class II antibodies or unlabeled analogs. Cop 1 exhibited the most extensive and fast binding to antigen-presenting cells. In addition, Cop 1 inhibited the binding of biotinylated derivatives of BP and of p84-102 to the MHC class II molecules and even displaced these antigens when already bound. Thus, these results suggest that Cop 1 indeed competes with BP for MHC binding and, thereby, inhibits T-cell responses to BP. The binding of Cop 1 to different DR alleles, probably because of its multiple MHC binding motifs, may indicate its potential as a broad-spectrum drug for multiple sclerosis.