Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1-358), followed by an 18 kDa peptide-binding domain (amino acids 359-494) and a C-terminal 10 kDa fragment (amino acids 495-609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359-610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFalpha(tumour necrosis factor alpha), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70-CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.
SUMMARYA non-cognate mechanism of protection against human immunode®ciency virus-1 (HIV-1) infection involves up-regulation of b-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modi®ed targeted lymph nodes (TLN) route with recombinant simian immunode®ciency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte± macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced signi®cant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage in¯ammatory protein (MIP)-1a and MIP-1b, and down-modulation of the proportion of cells expressing CCR5 (r=0 . 737, P<0 . 05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a signi®cant inverse correlation with the CD8-SF or the concentration of the three b-chemokines (r=0 . 831 and 0 . 824, P<0 . 01), but a positive correlation between the proportion of CCR5 + cells and SIVmac RNA (r=0 . 613, P=0 . 05). These results demonstrate for the ®rst time in vivo that immunization up-regulates b-chemokines, which may down-modulate CCR5 co-receptors, and both functions are signi®cantly correlated with the viral load. Hence, the non-cognate b-chemokine±CCR5 mechanism should be considered as complementary to speci®c immunity in vaccination against HIV.
Recurrent aphthous stomatitis (RAS) is the most common disease of the oral mucosa, affecting at least 10% of the general population [1]. The onset of RAS usually presents during adolescence, and the course of the disease is characterized by recurrences followed by remissions. The disease may persist for many years and varies from minor ulcers, which may cause transient discomfort, to major ulcers which are associated with pain, inability to eat and loss of weight [2].The aetiology of RAS has not been determined, but Streptococcus sanguis or its L-form [3,4] has been implicated, as has autoimmunity to the oral mucosal homogenate [5][6][7]. A common or cross-reactive antigen between streptococci and oral epithelium has been suggested [6][7][8][9] and demonstrated between the streptococcal 60-65 kD heat shock protein (HSP) and oral mucosal tissue [10]. Significant increase in serum antibodies to HSP has been detected in patients with RAS [10].Heat shock proteins (HSP) are a group of highly conserved proteins found in eukaryotic and prokaryotic cells, including Gram-positive and Gram-negative micro-organisms [11,12]. Viruses can enhance the production of host HSP. The high degree of homology between microbial and human HSP 60 [13] has led to the concept that molecular mimicry between the microbial and self HSP may be involved in the pathogenesis of autoimmune diseases [14]. A comprehensive investigation of T-cell epitopes within the 65 kD mycobacterial-and 60 kD human HSP-derived peptides has identified four T-cell epitopes specific for Behcet's disease, in which oral ulceration is the most consistent manifestation [15]. All but one of the four peptides (amino acids 219-233) showed significantly greater stimulation of lymphocytes from patients with Behcet's disease than those from RAS. However, the investigation raised the possibility that another peptide (amino acids 91-105) might specifically stimulate lymphocytes from RAS and not Behcet's disease. Indeed, specific lymphoproliferative responses are stimulated with peptide 91-105 in RAS [16]. A comparative investigation with the homologous human 60 kD HSP peptide 116-130 also revealed significantly greater lymphoproliferative responses in RAS than in controls.The objectives of this investigation in patients with RAS were to define the critical residues within the T-cell epitope 91-105, and to investigate the role of HLA class I and II restriction elements in the lymphoproliferative response. The possibility that g d T cells may be involved was also explored. 318 Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis SUMMARYThe 65 kD heat shock protein (HSP) has been implicated in the aetiology of recurrent aphthous stomatitis (RAS). We have previously demonstrated that peptide 91-105 derived from the sequence of mycobacterial 65 kD HSP stimulates specifically lymphocytes from patients with RAS. In this investigation, we show that both CD4 + and CD8 + T cells were significantly stimulated with mycobacterial peptide 91-105. In contrast, the human h...
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