The biography of the immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies.

BACKGROUND: The historical basis and contemporary evidence for the use of immune strategies for prevention of malignancies are reviewed. Emphasis is focussed on the Febrile Infections and Melanoma (FEBIM) study on melanoma and on malignancies that seem to be related to an overexpression of human endogenous retrovirus K (HERV-K). DISCUSSION: It is claimed that, as a result of recent observational studies, measures for prevention of some malignancies such as melanoma and certain forms of leukaemia are already at hand: vaccination with Bacille Calmette-Guérin (BCG) of new-borns and vaccination with the yellow fever 17D (YFV) vaccine of adults. While the evidence of their benefit for prevention of malignancies requires substantiation, the observations that vaccinations with BCG and/or vaccinia early in life improved the outcome of patients after surgical therapy of melanoma are of practical relevance as the survival advantage conferred by prior vaccination is greater than any contemporary adjuvant therapy. SUMMARY: The reviewed findings open a debate as to whether controlled vaccination studies should be conducted in patients and/or regions for whom/where they are needed most urgently. A study proposal is made and discussed. If protection is confirmed, the development of novel recombinant vaccines with wider ranges of protection based, most likely, on BCG, YFV or vaccinia, could be attempted.

Is a hypothetical melanoma-like neuromelanin the underlying factor essential for the aetiopathogenesis and clinical manifestations of multiple sclerosis?

BACKGROUND: Multiple sclerosis (MS) has undergone a significant increase in incidence in the industrialised nations over the last 130 years. Changing environmental factors, possibly infections or a lack of or altered timing of them, determine the prevalence of the disease. Although a plethora of aetiological factors, clearly evident in a group of children with MS, appear relevant, there may nevertheless be a single factor essential for the aetiopathogenesis and clinical manifestation of MS. DESCRIPTION AND DISCUSSION: This hitherto unknown factor is postulated to be a 'melanoma-like neuromelanin' (MLN) dependent on the activation of a gene for syncytin-1. An involvement of MLN could explain the diverse findings in the epidemiology, immunology and pathology of MS, requiring a consideration of a complex infectious background, the human leucocyte antigens, as well as cosmic radiation causing geomagnetic disturbances, vitamin D deficiency, smoking, and lower levels of uric acid. SUMMARY: In principle, the MLN-based concept is a unifying one, capable of explaining a number of characteristics of the disease. To date, MLN has not been addressed in studies on MS and future work will need to be done on human patients, as there is little or no neuromelanin (the precursor of MLN) in the animals used as experimental models in the study of MS.

Paradigms in multiple sclerosis: time for a change, time for a unifying concept.

It has recently been suggested that, rather than being an autoimmune disease, multiple sclerosis (MS) is an example of a neurocristopathy, a pathological process resulting from a faulty development of the neural crest. Whilst several characteristics of the disease suggest a neurocristopathy, other aetiological factors require consideration, including hygiene-related factors that alter the immune responses to common pathogens resulting in an eclipse of immune reactivity that could protect against MS, the possible role of human endogenous retroviruses (HERVs) in pathogenesis and autoimmune phenomena, HLA polymorphism, vitamin D levels before and after birth and immune repair mechanisms. A postulated aetiological factor in MS, associated with altered vitamin D metabolism and abnormal HERV expression, is a long-lasting disturbed redox regulation in the biosynthesis of a melanoma-like melanin pigment. Although intensive further studies on melanin pigments in nerve tissue in MS are required, the known properties of a pathological form of such pigments in melanoma could explain a number of observations in MS, including the impact of light, UV-light, and vitamin D, and could explain the clinical manifestations of MS on the basis of an oscillating process of oxidative charge and discharge of the pigments and a threshold phenomenon with a change of the quasi-catalytic function of the pigment from destroying reactive oxygen radicals or species to transforming them to more harmful long-persisting highly reactive species. Taken together with the consequences of an adaptive process in partly demyelinated neurons, resulting in an increase in number of mitochondria, and the impact of stressful life events, these conditions are necessary and sufficient to explain the disease process of MS with its spatial (plaques) and temporal (attacks and remissions) characteristics. This suggested unifying concept of the pathogenesis of MS may open perspectives for prevention, diagnosis and therapy. In particular, prevention may be achieved by vaccinating against Epstein-Barr virus in early childhood.

Multiple sclerosis: are protective immune mechanisms compromised by a complex infectious background?

The immunological background of multiple sclerosis (MS) manifests as an altered reactivity against a diverse range of infections, particularly with the Epstein-Barr virus. Although this could be only an epiphenomenon of a more generalised dysfunction of the immune system in MS, it is also possible that a complex infectious background forms the basis of a specific immune dysregulation finally causing the disease. It is thus suggested that the complex infectious background bears the key for an understanding of the immune pathogenesis of the disease. It appears probable that improved standards of hygiene cause regulatory defects in the immune system, allowing the abnormal expression of human endogenous retroviral (HERV) genes. On the basis of epidemiological observations we describe how a failure of expansion or an eclipse of a subfraction of self-antigen-specific CD8(+) T cells mediating immune repair, and a deleterious mode of action of HERV gene products, could underlie the pathogenesis of MS.

Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.

Can prior vaccinations against certain infections confer protection against developing melanoma?

Currently available, relatively safe vaccines may help tackle this serious and increasing public health problem.

Immunotherapy for malignant melanoma--tracing Ariadne's thread through the labyrinth.

A working group (FEBIM) within the European Organisation for Research and Treatment of Cancer undertook extensive studies on the possible association of infectious diseases and the risk of malignant melanoma. These studies provided evidence that several infectious diseases and also some vaccines including the anti-tuberculosis vaccine, BCG, derived from Mycobacterium bovis, confer a significant level of protection against this form of cancer. In recent years, the importance of immunoregulatory networks in the establishment of tolerance to tumour antigens and the key role of the innate immune system in the development of such networks have been recognised. The molecular patterns of micro-organisms activate pattern recognition receptors on antigen presenting cells and determine the qualitative nature of the ensuing immune response. Bacteria in the actinomycetales family, notably members of the genus Mycobacterium, exhibit particularly powerful adjuvant activity and profoundly affect underlying patterns of immune reactivity. In particular, there is growing evidence that a heat-killed preparation of a strain of Mycobacterium vaccae is able to down-regulate patterns of immune reactivity that favour the tumour and to induce those that lead to anti-cancer immune responses. The results of preliminary clinical observations with melanoma patients, and published studies on other cancers, point to the need for more formal clinical trials.

Is the risk of multiple sclerosis related to the 'biography' of the immune system?

Multiple sclerosis (MS) with onset in childhood offers a unique opportunity to study the infectious background of this disease but the immune reactions against infectious agents in such children have only recently been investigated. These and other epidemiological studies strongly implicate involvement of one or more infectious agents in the aetiology of MS, with Epstein-Barr virus (EBV) being the prime candidate. Rather than being the actual cause of MS, it is more probable that these agents are involved in the development of immunoregulatory pathways. These pathways, if disturbed by hygiene-related factors including an altered sequence of infections, may generate and maintain a deficit within the immunological network that facilitates, to particular early events in the development of MS, preceding the onset of MS disease by years or a decade. A framework that can serve as a guide for further epidemiological, immunologic and molecular biologic investigations is formulated. This approach may shed light on the complex natural history of MS and may lead to rational preventive and therapeutic strategies. It is possible that, in the future, MS could be prevented by vaccination against EBV in early childhood; the framework is of relevance to the design of an appropriate type of vaccine.

Common infectious agents in multiple sclerosis: a case-control study in children.

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.

Improved serological diagnosis stresses the major role of Campylobacter jejuni in triggering Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a postinfectious autoimmune polyradiculoneuropathy. The most frequent antecedent pathogen is Campylobacter jejuni, followed by cytomegalovirus. However, more than 40% of GBS cases currently cannot be attributed to triggering events. This might be due to the shortcomings of the serological assays used for diagnosing infections, in particular for C. jejuni. In our study investigating 36 patients with acute GBS, standard serological methods identified the triggering viral or bacterial etiology in only 25% of cases. However, using a highly specific enzyme-linked immunosorbent assay based on two recombinant outer antigens encoded by C. jejuni genes Cj0017 (P39) and Cj0113 (P18), we found serological evidence of a preceding C. jejuni infection in 80.6% of the patients but in only 3.5% of the controls. We conclude that the role of C. jejuni in triggering GBS has been greatly underestimated.

Protection against melanoma by vaccination with Bacille Calmette-Guerin (BCG) and/or vaccinia: an epidemiology-based hypothesis on the nature of a melanoma risk factor and its immunological control.

A multicentre case-control study conducted by the FEBrile Infections and Melanoma (FEBIM) group has demonstrated a reduced risk of melanoma associated with Bacille Calmette-Guerin (BCG) and/or vaccinia vaccination in early childhood and/or with infectious diseases later in life. This has led to the recognition of a new risk indicator of melanoma; namely 'not being vaccinated with either with BCG or vaccinia'. On the basis of these findings, we propose a hypothesis of immune surveillance for melanoma induced or enhanced by prior contacts with pathogens unexpectedly cross-reactive to a cellular 'marker of melanoma risk'. The reduced risk of melanoma due to BCG and vaccinia, as well as certain common causes of infectious disease, is shown to be associated with antigenic determinants exhibiting sequence homologies with the HERV-K-MEL-antigen. The latter is a product of a pseudo-gene that is closely associated with the env-gene of the endogenous human retrovirus K (HERV-K). A suppressive immune reaction appears to inhibit the expression of endogenous retroviral genes, such as the HERV-K env-gene, that could otherwise result in malignant transformation years or even decades later. The HERV-K env-protein has homologous amino acid sequences with the human nuclear factor Oxygen Responsive Element Binding Protein (OREBP) that controls the expression of glutathione peroxidase. The formation of this and other redox-enzymes, needed to maintain appropriate levels of the normal intracellular redox potential, seems to be suppressed by the OREBP-homologous protein. The present hypothesis is in accordance with the concept that immune dysregulation due to adverse environmental impacts is a risk factor not only for some autoimmune disorders, as previously described, but also for certain malignancies such as melanoma.

Impact of conventional chemotherapy on levels of antibodies against vaccine-preventable diseases in children treated for cancer.

Intensive chemotherapy in children with malignancies causes partial immune deficiency, including long-term impairment of humoral immunity. We investigated the levels of antibodies against measles, mumps, polio, rubella, diphtheria, tetanus, and Haemophilus type b (Hib) in 139 children at the time of diagnosis of the malignant disease, during chemotherapy, after cessation of intensive treatment, and after re-vaccination. In general, cytostatic therapy resulted in a significant lowering of antibody levels. A decline of antibodies below the protective level as a consequence of cytostatic treatment was observed in 6% of the children for measles and mumps, in 18%, 12%, and 25% for polio types 1, 2, and 3, and in 21% for diphtheria. By contrast, rubella and tetanus antibodies remained within the protective range in all cases of this study. Re-vaccination 3 to 5 months after cessation of chemotherapy produced antibody levels about as high as those measured prior to therapy. Only 6 out of 83 children with previously positive antigen titres did not respond to re-vaccination. Vaccination or re-vaccination failed in 5 of 13 non-responders for more than 1 antigen, indicating a decreased reactability to vaccinations in some patients.

Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study.

Various forms of immunotherapy utilizing bacille Calmette-Guérin vaccine or vaccinia vaccine have been evaluated in clinical trials on melanoma patients. The effect of the "natural" application of these vaccinations, administered to provide protection against tuberculosis and smallpox, has, however, never been studied in epidemiologic investigations on risk factors for melanoma. In a case-control study comprising 11 institutions in seven countries we recruited 603 incident melanoma cases and 627 population controls frequency matched to the cases with respect to sex, age, and ethnic origin within each center to assess this relationship to obtain insights into the prevention of melanoma. Exposure information, incorporating also detailed ascertainment of potential confounding variables, was obtained in standardized personal interviews at the study subject's home. We found an inverse association between melanoma risk and previous bacille Calmette-Guérin vaccine/vaccinia vaccination depicted by an adjusted odds ratio of 0.44 (95% confidence interval: 0.26-0.72) for those vaccinated against tuberculosis and smallpox compared with subjects without a positive history of either vaccination. A variety of subgroup analyses showing a consistent pattern of results make it unlikely that the observed inverse association is a spurious finding. We conclude that bacille Calmette-Guérin vaccination and vaccinia vaccination may lower melanoma risk. Current immunologic theory of melanoma development provides a sound basis for understanding the biologic plausibility of the findings that have to be confirmed in future studies.