Nature has provided us with infections - acute and chronic - and these infections have both harmful and beneficial effects on the human system. Worldwide, a number of chronic infections are associated with a risk of cancer, but it is also known that cancer regresses when associated with acute infections such as bacterial, viral, fungal, protozoal, etc. Acute infections are known to cure chronic diseases since the time of Hippocrates. The benefits of these fever producing acute infections has been applied in cancer vaccinology such as the Coley's toxins. Immune cells like the natural killer cells, macrophages and dendritic cells have taken greater precedence in cancer immunity than ever before. This review provides an insight into the benefits of fever and its role in prevention of cancer, the significance of common infections in cancer regression, the dual nature of our immune system and the role of the often overlooked primary innate immunity in tumor immunology and spontaneous regression of cancer.
Murine antibody responses to heterologous insulins are under H-2-linked immune response (Ir) gene control. We have found that the immune response to insulin in adjuvant can be inhibited by prior i.v. injection of soluble insulin. The effect of i.v. injection of insulin is antigen-specific and dose-dependent and requires the same doses of insulin that are immunogenic if administered with adjuvant. In addition, the inhibitory effect of soluble insulin is dependent upon the route of injection; if soluble insulin is injected i.p., the subsequent response to insulin in adjuvant is augmented rather than inhibited. Unresponsiveness requires at least 4 days after i.v. injection to develop and once induced, it is maintained for 4 wk or more. Unresponsiveness is caused by T cell, but not B cell, tolerance, and we have been unable to demonstrate any role for suppressor T cells in this unresponsiveness. More importantly, analysis of the ability of numerous insulin variants to induce unresponsiveness in several H-2k and H-2b strains of mice has demonstrated that only the variants that were immunogenic in a given strain when administered with adjuvant were able to cause tolerance. This report is, to our knowledge, the first describing that induction of helper T cell tolerance, like the induction of immunity, is controlled by H-2-linked Ir genes.
Three human T cell lines specific for the A loop of beef insulin were studied to determine the requirements for Ag processing. The data show that the conformation of the A loop of insulin is required for recognition and that the B chain of insulin per se is not necessary for this response. Processing of native insulin was required for responses of all three T cell lines; however, each displayed a different pattern of sensitivity to inhibition of processing and aldehyde fixation of APC. A peptide comprised of two disulfide-linked A chains was partially stimulatory when presented by fixed APC whereas A chain monomers and disulfide-linked A and B chain peptides were not. The response to native insulin, peptides, and A chain dimers was sensitive to chloroquine suggesting that none of these moieties is the terminal processed peptide recognized by insulin immune T cells. The unique patterns of fine specificity, processing requirements, and recognition of aldehyde-fixed antigen-MHC for each T cell line suggest the hypothesis that Ag processing leads to heterogeneity of the T cell repertoire for a single epitope of insulin.
Synthetic polypeptides corresponding to restricted regions of the B chain of insulin were used to evaluate immune response gene control of guinea pigs immune to native insulin. The amino acids necessary for recall of immune memory were assessed at the level of the T cell by use of peptides 8 to 16 amino acids in length, representative of the amino terminus of the insulin B chain to induce antigen-specific proliferation and help for antibody formation. A single histidine residue in the 10th position of the B chain is critical for T cell activation. In addition, immune response genes operating in the macrophage discern the presence or absence of this residue and activate the appropriate T cell clones. Although receptor V region sharing may exist for T and B cells immune to globular proteins, it cannot be demonstrated by antigen specificity, since T proliferation and generation of T helper cells in response to intact insulin can be elicited by synthetic fragments that do not correspondingly induce antibodies that recognize the native molecule.
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