Retrospective comparisons of the prevalence and age, where appropriate, of some childhood infectious illnesses and vaccinations, together with serological evidence for exposure to 16 viruses, many of which have previously been implicated in the aetiology of multiple sclerosis (MS) were made in 177 patients with acute optic neuritis, other recent isolated demyelinating episodes or established MS and 164 controls. The expected high frequency of HLA-DR2 in patients with demyelinating disease was matched by preselection of normal controls with this antigen (DR2+); the remaining individuals were classified as HLA-DR2 negative/DR3 positive (DR3+) or HLA-DR2 and 3 negative (DR2/3 -). Cases were compared with controls, collectively and in analyses restricted to each genetic group; these comparisons were repeated considering the three categories of patients with demyelination and two control populations separately. All DR2+, DR3+ and DR2/3 - individuals were compared in a single analysis to assess the effect of HLA type itself on the results. Patients with demyelinating disease had rubella and measles at a later age and reported mumps infection more frequently than controls. Age of typhoid vaccination and duration of exposure to domestic dogs was higher in all cases than controls. Age of measles and mumps, but not rubella, was higher in DR2+ cases than controls; but differences were not observed in the other genetic groups. Higher rubella antibody titres were present in all cases than controls and in analyses confined to DR2+ individuals in whom higher Epstein Barr virus antibody titres were also present. Measles haemagglutination inhibition and parainfluenza I antibody titres were increased and influenza A antibodies detected less frequently in all patients with optic neuritis and those with DR2 compared with appropriate controls; influenza B antibody titres were lower in all DR2+ cases than controls. Higher adenovirus and varicella zoster antibody titres were present in DR2/3- patients with demyelination and other neurological diseases compared with normal controls. Overall, older age of infection and higher antibody titres were observed more often in patients with optic neuritis, in particular DR2+ cases, than other individuals with demyelination or controls. Our serological results are consistent with the presence of abnormal HLA-immunological reactivity in patients with MS but cannot be explained only by an effect of DR type itself; age at which susceptible individuals develop some common childhood infections may also influence the subsequent development of the disease.

Cryotherapy offers a minimally invasive treatment option for the management of both irresectable and localized prostate, liver, pulmonary and renal tumors. The anti-neoplastic effects of cryotherapy are mediated by direct tumor lysis and by indirect effects such as intracellular dehydration, pH changes, and microvascular damage resulting in ischemic necrosis. In this study, we investigated whether percutaneous cryoablation of lung metastasis from renal cell carcinoma (RCC) in combination with aerosolized granulocyte-macrophage colony stimulating factor (GM-CSF) can induce systemic cellular and humoral immune responses in 6 RCC patients. Peripheral blood mononuclear cells (PBMC) were sequentially studied up to 63 days post cryoimmunotherapy (CI). PBMC from pre and post CI were phenotyped for lymphocyte subsets and tested for cytotoxicity and IFNγ Elispots directed at RCC cells. Humoral responses were measured by in vitro antibody synthesis assay directed at RCC cells. The immune monitoring data showed that CI induced tumor specific CTL, specific in vitro anti-tumor antibody responses, and enhanced Th1 cytokine production in 4 out of 6 patients. More importantly, the magnitude of cellular and humoral anti-tumor response appears to be associated with clinical responses. These pilot data show that CI can induce robust and brisk cellular and humoral immune responses in metastatic RCC patients, but requires further evaluation in optimized protocols.

HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p2419–27, TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.