Incorporating Gravity Model Principles into Disease Mapping

The space‐time variation of disease risk, considering the closeness and availability of care units, is studied by a hierarchical Bayesian model in a gravitational formulation. The pattern of mortality for Hodgkin's lymphoma over the last twenty‐five years in the Tuscany region and the evaluation of the consequences of distance from the nearest radiation‐therapy center are described. Results show a decrease in mortality for Hodgkin's lymphoma and the attraction exercised by each care units.     

Monitoring the level of complement components during autologous blood stem cell transplantation in patients with malignant lymphomas

The aim of this study was to determine the complement functions, the serum levels of the complement components C3 and C4, and circulating immune complexes during autologous blood stem cell transplantation. Seventeen lymphoma patients receiving transplants between 1997 and 2001 were involved in this study. High-dose chemotherapy with or without total body irradiation was used for conditioning. The transplantation resulted in complete remission without complications in 14 patients. Early relapse developed in one case and two nonrelapsed patients suffered from serious toxic infection early posttransplant. Normal values of CH50, C3, C4, and immune complexes in sera of patients were detected on day –7, before the conditioning (day of transplantation was determined as day 0). After the conditioning, on day –2, the levels of the CH50, C3, and C4 decreased significantly (p<0.05) in all patients compared with the starting values. The CH50, C3, and C4 levels exceeded the starting values in the noninfected patients from day +7. In two patients suffering from toxic infection, significantly elevated complement levels were documented early posttransplant. In the relapsed patient a significant decrease of the complement parameters was documented posttransplant accompanied by a significant elevation in the immune complex level. The results show alteration in the complement parameters during transplantation, but in the complication-free cases this remained within the normal ranges. However, an unusual elevation seemed to be the sign of infection, and the significant decrease seemed to indicate a relapse.     

Humoral detection of leukaemia-associated antigens in presentation acute myeloid leukaemia

The serological analysis of recombinant cDNA expression libraries (SEREX) technique was used to immunoscreen a testes cDNA expression library with sera from newly diagnosed acute myeloid leukaemia (AML) patients. We used a testis cDNA library to aid our identification of cancer-testis (CT) antigens. We identified 44 antigens which we further immunoscreened with sera from AML, chronic myeloid leukaemia (CML), and normal donors. Eight antigens were solely recognised by patient sera including the recently described CT antigen, PASD1, and the cancer-related SSX2 interacting protein, SSX2IP. RT-PCR analysis indicated that we had identified three antigens which were expressed in patient bone marrow (BM) and peripheral blood (PB) but not in normal donor samples (PASD1, SSX2IP, and GRINL1A). Real-time PCR (RQ-PCR) confirmed the restricted expression of PASD1 in normal donor organs. Antigen presentation assays using monocyte-derived dendritic cells (mo-DCs) showed that PASD1 could stimulate autologous T-cell responses, suggesting that PASD1 could be a promising target for future immunotherapy clinical trials.     

Rapid expression of vaccine proteins for B-cell lymphoma in a cell-free system

The idiotype (Id)-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins are potential vaccines for immunotherapy of B-cell lymphoma. In this study, four vaccine candidates were constructed by fusing murine GM-CSF to the amino- or carboxy-terminus of the 38C13 murine B-lymphocyte Id scFv with two different arrangements of the variable regions of the heavy chain and light chain (VL-VH and VH-VL). scFv (VH-VL) and GM-CSF/scFv fusion proteins were expressed in an Escherichia coli cell-free protein synthesis system. In order to promote disulfide bond formation during cell-free expression, cell extract was pretreated with iodoacetamide (IAM), and a sulfhydryl redox buffer composed of oxidized and reduced glutathione was added. The E. coli periplasmic disulfide isomerase, DsbC, was also added to rearrange incorrectly formed disulfide linkages. The 38C13 B-lymphocyte Id scFv was expressed with 30% of its soluble yield in active form (43 microg/ml) when tested with an anti-idiotypic mAb, S1C5, as the capture antibody in radioimmunoassay. It was found that the amino-terminal GM-CSF fusion proteins, GM-VL-VH and GM-VH-VL, showed much higher activity than the carboxy-terminal GM-CSF fusion proteins, VL-VH-GM and VH-VL-GM, in stimulating the cell proliferation of a GM-CSF-dependent cell line, NFS-60. Between the two amino-terminal GM-CSF fusion proteins, GM-VL-VH showed a higher total and soluble yield than GM-VH-VL.     

Lymphoma immunophenotyping: "borderline" lymphomas

Immunophenotyping of B-cell lymphoproliferative disorders is indispensable, especially in disorders with CD19(+) CD5(+) B lymphocytes, where we have to make the distinction between low grade neoplasia, such as chronic lymphocytic leukemia with CD23(+) malignant lymphocytes, and aggressive neoplasia such as mantle cell lymphoma with CD23(-) malignant lymphocytes. We found some cases of CD19(+) CD5(+) lymphoproliferative disorders that do not meet all criteria for diagnosis of chronic lymphocytic leukemia or mantle cell lymphoma. For instance, we found cases with a low or no expression of CD23, asociated with absence of expression of FMC7 and surface immunoglobulins. These cases could be classified as "borderline" CD19(+) CD5(+) B cell lymphoproliferative disorders, with an intermediate neoplasic grade.     

The peptide molecular links between the central nervous and the immune systems

Summary. The central nervous system (CNS) and the immune system were for many years considered as two autonomous systems. Now, the reciprocal connections between them are generally recognized and very well documented. The links are realized mainly by various immuno- and neuropeptides. In the review the influence of the following immunopeptides on CNS is presented: tuftsin, thymulin, thymopoietin and thymopentin, thymosins, and thymic humoral factor. On the other side, the activity in the immune system of such neuropeptides as substance P, neurotensin, some neurokinins, enkephalins, and endorphins is discussed.     

Targeting properties of an anti-CD16/anti-CD30 bispecific antibody in an in vivo system

Bispecific antibodies are currently being used in clinical trials in increasing numbers in the areas of breast cancer, prostate cancer, non-Hodgkin's lymphoma and Hodgkin's lymphoma. We have previously performed two clinical trials in patients with Hodgkin's disease with an anti-CD30/anti-CD16 bispecific antibody and demonstrated a 30% response rate in a cohort of patients otherwise resistant to standard therapeutic modalities. However, no surrogate marker could be defined in these trials indicative of optimal antibody dosing/scheduling or predictive for favorable response. In order to evaluate accurately the potential biodistribution properties of bispecific antibody in patients, we have performed a detailed analysis of the binding properties and animal model in vivo characteristics of these constructs. For this purpose, the parental antibodies (anti-CD30 and anti-CD16) and the bispecific antibody (anti-CD30/anti-CD16) were radiolabeled with either ¹²⁵I or ¹¹¹In. Antibody integrity and binding properties after labeling were confirmed by Scatchard plot and Lindmo analysis. ¹¹¹In-labeled antibodies revealed superior targeting properties in a standard SCID mouse tumor model. Both the bivalent parental anti-CD30 monoclonal antibody and the monovalent anti-CD30/anti-CD16 bispecific antibody showed excellent uptake in CD30⁺ tumors which did not differ significantly between the two (maximum uptake 16.5% ± 4.2% vs. 18.4% ± 3.8% injected dose/gram tissue). The equivalent targeting properties of the bispecific antibody compared with the parental anti-CD30 antibody encourages the further clinical development of this bispecific antibody, and might help to explain the clinical responses seen with this antibody so far in patients suffering from Hodgkin's disease. Received: 26 October 2000 / Accepted: 15 December 2000     

Three spontaneous lymphomas in a colony of cotton-top tamarins (Saguinus oedipus)

Cotton-top tamarins are well known for their prevalence to idiopathic colitis and adenocarcinomas. At the same time, information on the incidence of spontaneous lymphomas in this highly endangered species is rare. Records, 212 in total, of cotton-top tamarins (Saguinus oedipus) necropsied at the German Primate Centre between 1979 and 1998 were viewed to establish the prevalence of lymphoid neoplasms. Neoplastic lymphoid cell growth was mentioned in three necropsy records. Immunohistology was performed in all three cases on the remaining formalin-fixed, paraffin-embedded tissue using antibodies against CD20, CD3, lysozyme, Ki-67, IgM, IgG, kappa, lambda and EBNA-2. Combining histological and immunohistological results, the lymphomas could be differentiated into two low-grade T-cell lymphomas and one high-grade multicentric polymorphic B-cell lymphoma. This corresponds to a 1.4% incidence of lymphomas in our cotton-top tamarin population over a period of 19 years. Although frozen material was not available and virological testing could not be carried out, clinical or histological evidence did not support an aetiological role of Herpes (H.) saimiri, H. ateles, simian T-cell leukaemia virus type 1 (STLV-1) or Epstein-Barr-related herpesvirus in any of these cases. The lymphomas were considered to be spontaneous.     

Molecular Mechanisms Involved in the Aging of the T-cell Immune Response

T-lymphocytes play a central role in the effector and regulatory mechanisms of the adaptive immune response. Upon exiting the thymus they begin to undergo a series of phenotypic and functional changes that continue throughout the lifetime and being most pronounced in the elderly. The reason postulated for this is that the dynamic processes of repeated interaction with cognate antigens lead to multiple division cycles involving a high degree of cell differentiation, senescence, restriction of the T-cell receptor (TCR) repertoire, and cell cycle arrest. This cell cycle arrest is associated with the loss of telomere sequences from the ends of chromosomes. Telomere length is reduced at each cell cycle, and critically short telomeres recruit components of the DNA repair machinery and trigger replicative senescence or apoptosis. Repetitively stimulated T-cells become refractory to telomerase induction, suffer telomere erosion and enter replicative senescence. The latter is characterized by the accumulation of highly differentiated T-cells with new acquired functional capabilities, which can be caused by aberrant expression of genes normally suppressed by epigenetic mechanisms in CD4+ or CD8+ T-cells. Age-dependent demethylation and overexpression of genes normally suppressed by DNA methylation have been demonstrated in senescent subsets of T-lymphocytes. Thus, T-cells, principally CD4+CD28^null T-cells, aberrantly express genes, including those of the KIR gene family and cytotoxic proteins such as perforin, and overexpress CD70, IFN-γ, LFA-1 and others. In summary, owing to a lifetime of exposure to and proliferation against a variety of pathogens, highly differentiated T-cells suffer molecular modifications that alter their cellular homeostasis mechanisms.