Alessio Annovazzi

99mTc-interleukin-2 scintigraphy for the in vivo imaging of vulnerable atherosclerotic plaques

PurposeSeveral histopathological studies have demonstrated that vulnerable plaques are enriched in inflammatory cells. The aims of this study were: (1a) to test the ability of 99mTc-labelled interleukin-2 (99mTc-IL2) to bind to IL2R-positive (IL2R+) cells in carotid plaques and (1b) to correlate the plaque uptake of 99mTc-IL2, measured in vivo, with the number of IL2R+ cells within the plaque, measured ex vivo by histology (transversal study, TS), and (2) to evaluate changes in 99mTc-IL2 uptake in plaques, before and after treatment with a statin or a hypocholesterolaemic diet (longitudinal study, LS).MethodsUltrasound scan was performed for plaque characterisation and localisation. Fourteen patients (16 plaques) eligible for endoarterectomy were recruited for the TS and underwent 99mTc-IL2 scintigraphy before surgery. Nine patients (13 plaques) were recruited for the LS; these patients received atorvastatin or a standard hypocholesterolaemic diet and 99mTc-IL2 scintigraphy was performed before and after 3 months of treatment.ResultsThe degree of 99mTc-IL2 uptake was expressed as the plaque/background (T/B) ratio. In patients from TS, T/B ratios correlated with the percentage of IL2R+ cells at histology (r=0.707; p=0.002) and the number of IL2R+ cells at flow cytometry (r=0.711; p=0.006). No correlations were observed between ultrasound scores and either scintigraphic or histological findings. In patients from the LS, the mean 99mTc-IL2 uptake decreased in statin-treated patients (1.75±0.50 vs 2.16±0.44; p=0.012), while it was unchanged in the patients on the hypocholesterolaemic diet (2.33±0.45 vs 2.34±0.5).Conclusion99mTc-IL2 accumulates in vulnerable carotid plaques; this accumulation is correlated with the amount of IL2R+ cells and is influenced by lipid-lowering treatment with a statin.

Imaging active lymphocytic infiltration in coeliac disease with iodine-123-interleukin-2 and the response to diet

Abstract. Coeliac disease is diagnosed by the presence of specific antibodies and a jejunal biopsy showing mucosal atrophy and mononuclear cell infiltration. Mucosal cell-mediated immune response is considered the central event in the pathogenesis of coeliac disease, and untreated coeliac patients show specific features of T-cell activation in the small intestine. Here we describe the use of iodine-123-interleukin-2 scintigraphy in coeliac patients as a non-invasive tool for detection of lymphocytic infiltration in the small bowel and its use for therapy follow-up, and we demonstrate the specificity of binding of labelled-IL2 to activated lymphocytes by ex-vivo autoradiography of jejunal biopsies. 123I-IL2 was administered i.v. [74 MBq (2 mCi)], and gamma camera images were acquired after 1 h. Ten patients were studied with 123I-IL2 scintigraphy at diagnosis and seven were also investigated after 12–19 months of gluten-free diet. Results were expressed as target-to-background radioactivity ratios in six different bowel regions before and after the diet. At the time of diagnosis all patients showed a significantly higher bowel uptake of 123I-IL2 than normal subjects (P<0.003 in all regions). A significant correlation was found between jejunal radioactivity and the number of IL2R+ve lymphocytes per millimetre of jejunal mucosa as detected by immunostaining of jejunal biopsy (r2=0.66; P=0.008). Autoradiography of jejunal biopsies confirmed that labelled-IL2 only binds to activated T-lymphocytes infiltrating the gut mucosa. After 1 year of the diet, bowel uptake of 123I-IL2 significantly decreased in five out of six regions (P<0.03), although two patients still had a positive IL2 scintigraphy in one region. We conclude that 123I-IL2 scintigraphy is a sensitive non-invasive technique for assessing in vivo the presence of activated mononuclear cells in the bowel of patients affected by coeliac disease. Unlike jejunal biopsy, this method provides information from the whole intestine and gives a non-invasive measure of the effectiveness of the gluten-free diet.

123I-Interleukin-2 Scintigraphy: A New Approach to Assess Disease Activity in Autoimmunity

Several human chronic inflammatory diseases, such as organ specific autoimmune diseases, are characterized by a chronic, slowly progressing, mononuclear cell infiltration of the target organ with little increase of vascular permeability. This infiltration can precede the onset of clinical symptoms by several months or years. Tissue biopsies may not be easily applicable to every organ and may poorly represent the condition of the whole organ particularly in inflammatory bowel diseases and in type 1 diabetes (IDDM). Thus, the possibility to detect the presence and extent of mononuclear cell infiltration in vivo by simple scintigraphy may be of considerable clinical utility for diagnosis and followup of several chronic inflammatory diseases. Immunohistochemical studies of tissue biopsies in several chronic inflammatory diseases have revealed that the target tissue is infiltrated by mononuclear cells (mainly T-lymphocytes) and that 10-50% of these cells express interleukin-2 receptors (IL2R) as a sign of cell activation /1-5Λ We previously described the labeling of IL2 with I and its specificity for the in vivo detection of pancreatic mononuclear cell infiltration in two animal models of autoimmune type 1 diabetes, the Bio Breeding/Worcester (BB/W) rat 161 and the non-obese diabetic (NOD) mouse 111. In this study we describe for the first time the use of I-IL2 scintigraphy for the non-invasive evaluation of disease activity and extent in patients with several different chronic inflammatory diseases.

Prognostic relevance of pancreatic uptake of technetium-99m labelled human polyclonal immunoglobulins in patients with type 1 diabetes

Abstract. Insulin-dependent type 1 diabetes (IDDM) is caused by the autoimmune destruction of insulin-producing beta cells. Approximately 10%–20% of patients may benefit from adjuvant immunotherapy upon diagnosis of the disease in order to protect residual beta-cell function. It has been suggested that this subgroup of patients differs from others by virtue of the presence of residual pancreatic inflammation and beta-cell function. In this study we have investigated to what extent technetium-99m-labelled human polyclonal immunoglobulins (99mTc-HIG) accumulate in the pancreas of IDDM patients at the time of diagnosis and 1 year thereafter, with a view to ascertaining whether HIG scintigraphy is useful for the identification of IDDM patients with residual pancreatic inflammation. Patients with recent-onset IDDM (n=15) were investigated at the time of diagnosis and 1 year later, and ten age- and sex-matched normal subjects were also studied. Gamma camera imaging and target to background ratio, analysed blind by three independent readers, were used to quantify the radioactivity in the pancreatic region and findings were correlated with metabolic, immunological and clinical parameters. Seven out of 15 newly diagnosed IDDM patients showed a significant accumulation of radiolabelled HIG in the pancreas (pancreas/bone ratio higher than the mean +2SD of normal subjects). One year after diagnosis, pancreatic accumulation of HIG was still detectable in most IDDM patients who were positive at the time of diagnosis. Six out of seven patients with positive scintigraphy had a partial clinical remission. These results indicate that HIG scintigraphy at the time of onset of diabetes identifies a subset of patients with residual beta-cell function who may benefit from adjuvant immunotherapy.

Fas and Fas ligand-mediated apoptosis and its role in autoimmune diabetes

The relationship between Fas-mediated apoptosis and Type 1 diabetes is currently under investigation. Fas/Fas ligand interaction could be involved both in the insulitis process and in beta-cell death. Nevertheless, different mechanisms appear to be involved in human Type 1 diabetes and in NOD mice. In the present work, we review recent evidence of the role of the Fas/Fas ligand system in human and NOD mouse diabetes, describing possible hypotheses for its involvement in the pathogenesis of the disease, with possible implications for therapy and islet transplantation.

Scientific production and impact of nuclear medicine in Europe: how do we publish?

We performed a bibliometric search covering a 1-year period to evaluate the number and the scientific “weight” of nuclear medicine papers published from European as compared with other countries. The scientific impact of our discipline was evaluated according to the impact factor of each publication, and we also aimed to identify those countries and topics that are making the principal contributions to the development of our discipline. To this end, a search on MEDLINE (PubMed) was run to find all peer-reviewed articles published between April 2002 and May 2003, using isotope definitions as search terms. A total of 3,292 publications were identified. Of these, 650 were of no nuclear medicine interest, 229 were reviews and 82 had no country specified. In absolute numbers, Europe leads research in nuclear medicine (939 papers, 38.9%) followed by the USA (608 papers, 25.2%). Among European countries, Germany is the nation that is currently making the greatest contribution to the scientific production of nuclear medicine in Europe. Articles concerning the use of nuclear medicine in oncology account for more than one-quarter of all published nuclear medicine papers.

Biological Imaging for the Diagnosis of Inflammatory Conditions

Radiopharmaceuticals used for in vivo imaging of inflammatory conditions can be conveniently classified into six categories according to the different phases in which the inflammatory process develops. The trigger of an inflammatory process is a pathogenic insult (phase I) that causes activation of endothelial cells (phase II); there is then an increase of vascular permeability followed by tissue oedema (phase III). Phase IV is characterised by infiltration of polymorphonuclear cells, and a self-limiting regulatory process called apoptosis is observed (phase V). If the inflammatory process persists, late chronic inflammation takes place (phase VI). In some pathological conditions, such as organ-specific autoimmune diseases, chronic inflammation is present early in the disease.The aim of nuclear medicine in the field of inflammation/infection is to develop noninvasive tools for the in vivo detection of specific cells and tissues. This would allow early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or by other diagnostic tools, and could also be used to evaluate the state of activity of the disease during therapy. These potential applications are of great interest in clinical practice.In this review, we describe the various approaches that have been developed in the last 25 years of experience. Recent advances in the diagnosis of inflammatory processes have led to the development of specific radiopharmaceuticals that are intended to allow specific stage-related diagnosis.

Nuclear Medicine Imaging For Prediction or Early Assessment of Response to Chemotherapy in Patients Suffering From Breast Carcinoma

Reliable assays that could assess treatment response more rapidly or even predict responsiveness of breast tumours to chemotherapy would be very valuable as they would allow for adjustment of ineffective treatment and discontinuation of ineffective treatment in an early phase. As with effective cancer therapy, changes in tumour physiology, metabolism and proliferation do often precede volumetric changes routinely measured by morphological imaging modalities, for example, radiography and computerized tomography, assessment of these parameters by means of single photon emission computerized tomography (SPECT) or positron emission tomography may provide more sensitive and earlier markers of tumour cell death or growth inhibition. This paper reviews the available literature on the role of SPECT and PET in the measurement and visualisation of breast tumour metabolism (glucose utilization and protein synthesis rate), apoptosis induction and chemotherapy resistance mechanisms as predictors or early markers of tumour response or non-response to chemotherapeutic options in patients suffering from breast carcinoma.

Radiolabelled cytokines for imaging chronic inflammation

Diagnosis and particularly follow-up of chronic inflammatory disorders could be often difficult in clinical practice. Indeed, traditional radiological techniques reveal only structural tissue alterations and are not able to monitor functional changes occurring in tissues affected by chronic inflammation. The continuous advances in the knowledge of the pathophysioloy of chronic disorders, combined with the progress of radiochemistry, led to the development of new specific radiolabelled agents for the imaging of chronic diseases. In this scenario, cytokines, due to their pivotal role in such diseases, represent good candidates as radiopharmaceuticals.