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In 1.4% and 4.3%

[42]

(autoreactive T cells, autoantibodies) in the blood of patients with preclinical stages of tumors. Such early responses can be verified by retrospective and prospective studies of risk groups. Three retrospective studies with a greater cohort of risk persons (Table 8) as well as the results of Lubin et al. [31] have shown that up to now in 15 patients p53 AAb could be detected prior to the diagnosis of a tumor. The period of time before diagnosis of lung cancer (11 cases), ASL (2 cases), breast (1 case) and prostate cancer (1 case) was between 4 months and 11 years (on average 26 months). Of greater importance regarding the predictive value of AAb are prospective studies in risk groups. The study of persons with an endogeneous (e.g., Li-Fraumeni syndrome, mutations in BRCA genes, first degree relatives of patients with tumors, etc.) or exogeneous risk (occupational exposure to cancerous noxes) as well as patients with preneoplastic diseases (e.g., Barretts' oesophagus) or diseases associated with a higher risk of tumor development (e.g., some autoimmune diseases, Sweets' syndrome, gluten-sensitive enteropathy, etc.) may give further hints of the real specificity of defined AAb (esp. anti-p53) for the development of tumors. It has been shown that AAb to p53 and cyclin B1 are present in various risk groups in higher frequencies than in blood donors [32, 34, 42, 84]. The follow-up of positive persons will show whether defined AAb are specific enough in the screening for preneoplastic or microinvasive tumor lesions allowing an early diagnosis and an early intervention of cancer.

Further studies may confirm that some of the AAb described above are highly specific and predictive markers for tumors. But for the screening of risk groups the sensitivities of most AAb are too low. Even the highest frequencies of about 30-50% found in lung, colorectal, head and neck cancer (anti-p53, anti-p21ras) and breast cancer (anti-HER-2/neu) are not sufficient for a screening programme. A combined determination of two or more tumor specific AAb may resolve this problem. Therefore, a further evaluation of the relevance of known AAb specificities as well as the search for other diagnostically relevant AAb is necessary.

The strategies for identifying new tumor relevant AAb are: (1) Screening with defined autoantigens known to be aberrant or overexpressed in tumors. This has been shown for AAb against oncoproteins, p53 and cyclins; (2) screening of tumor sera by in direct immunofluorescence on tumor cell monolayer or other targets for identifying antibodies reactive with cell-cycle-dependent antigens or other antigens possibly involved in cell growth. This type of procedure has led to the detection of the new autoantigens SG2NA, CENP-F and HCC1; and (3) The immuno-screening of cDNA expression libraries is the most powerful method for primary screening (SEREX) or for identifying novel proteins detected by indirect immunofluorescence with tumor sera.

Taken together, the screening for an AAb response in tumor patients may lead to new diagnostic tumor markers and may be a simple and effective way to identify concomitantly CTL reactivity [61], Furthermore, as "reporters from the immune system" such AAb could be used to elucidate the nature of autoantigens which drive the immune response [85].

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