Quilty effect has the features of lymphoid neogenesis and shares CXCL13-CXCR5 pathway with recurrent acute cardiac rejections.

Quilty effect (QE) is a frequent, yet enigmatic feature of cardiac allograft, since it is apparently devoid of clinical significance, though its association with acute (A) rejection (R) is strongly suspected. It was observed in 126/379 biopsies from 22 patients during the first posttransplant year. Most grade (G)2R biopsies displayed a concomitant QE. The following features typical of QE were identified: (a) focal angiogenesis and lymphangiogenesis associated with bFGF, VEGF-C and VEGF-A expression, (b) marked infiltrate of CD4(+)T and CD20(+)B followed by CD8(+)T lymphocytes arranged around PNAd(+)HEV-like vessels. Most QE appear as distinct B-T-cell-specific areas with lymphoid follicles sometimes endowed with germinal center-like structures containing VCAM-1(+)CD21(+)FDC and CD68(+)macrophages, which frequently expressed CXCL13. These cells were also found in mantle-like zones, where small lymphocytes expressed CXCR5, otherwise in the whole area of not clustered lymphoid aggregates. CXCL13 was also expressed, in association with CD20(+)B lymphocyte recruitment, in G2R biopsies obtained from patients with recurrent AR. QE has features of a tertiary lymphoid tissue suggesting an attempt, by the heart allograft, to mount a local response to a persistent alloantigen stimulation resulting in aberrant CXCL13 production, as also occurs in recurrent AR. CXCL13-CXCR5 emerge as a common molecular pathway for QE and recurrent episodes of AR.

Endomyocardial infiltration by B and NK cells foreshadows the recurrence of cardiac allograft rejection.

Heart allograft outcome is unpredictable and acute rejection episodes still occur despite the improvement of immunosuppressive regimens. We therefore investigated whether the immunopathological profile of endomyocardial biopsies might underlie the variations in the clinical course of a graft. Biopsies from transplanted patients were analysed by histology, immunohistochemistry (associated with digital image analysis), confocal and electron microscopy to determine the type and the functional state of leukocytes infiltrating the myocardium, together with their ultrastructural features and those of the graft itself. In comparison with biopsies with grade 0R or grade 1R rejection, those from patients with grade 2R rejection displayed significant infiltration of macrophages, T lymphocytes, and CD83+ and DC-SIGN+ dendritic cells. Fifty-seven per cent were invaded by CD20+B lymphocytes, most of which expressed CD69 activation marker and cooperated in interleukin-12 production, and by CD69+CD94+NK cells expressing interferon-gamma. Ultrastructural signs of myocyte degeneration and microvessel rupture by NK cells were frequent. These patients developed recurrent episodes of acute allograft rejection. Endomyocardial B and NK infiltrates are involved in the dynamics of allograft rejection and are associated with a high risk of its recurrence. Immunopathological assessment of endomyocardial biopsies may thus serve to forecast the probable outcome of a heart allograft.

Low-dose interferon-gamma-producing human neuroblastoma cells show reduced proliferation and delayed tumorigenicity.

Interferon-gamma (IFN-gamma) directs T helper-1 cell differentiation and mediates antitumour effects in preclinical models. However, high-dose IFN-gamma is toxic in vivo, and IFN-gamma-transfected neuroblastoma (NB) cells secreting high amounts of the cytokine may be lost due to cell apoptosis or differentiation. Two human NB cell lines (ACN and SK-N-BE2(c)) differing as to genetic and phenotypic features were transfected with the human IFN-gamma gene and selected on the grounds of the low concentrations of IFN-gamma produced. In both IFN-gamma-transfected cell lines, autocrine and paracrine activation of IFN-gamma-mediated pathways occurred, leading to markedly reduced proliferation rate, to increased expression of surface HLA and CD40 molecules and of functional TNF binding sites. ACN/IFN-gamma cells showed a significantly delayed tumorigenicity in nude mice as compared to parental cells. ACN/IFN-gamma tumours were smaller, with extensive necrotic area as a result of a damaged and defective microvascular network. In addition, a significant reduction in the proliferation index was observed. This is the first demonstration that IFN-gamma inhibits in vivo proliferation of NB cell by acting on the tumour cell itself. This effect adds to the immunoregulatory and antiangiogenic activities operated by IFN-gamma in syngeneic tumour-bearing hosts.

Salivary carcinoma in HER-2/neu transgenic male mice: an angiogenic switch is not required for tumor onset and progression.

Morphologic examinations of salivary gland neoplasias arising in male BALB/c (H-2d) mice carrying the activated HER-2/neu (BALB-NeuT) indicate that expression of the oncogene product in the ductal-acinar structures results in a very human-like acinic cell adenocarcinoma with a smoldering course and infrequent metastatization. Typical and then atypical hyperplasia of ducts and acini preceded the rise of salivary tumors that originated from the confluence of multiple ductal hyperplastic foci, while hyperplastic acini behaved as an abortive preneoplastic lesion. The vascular network in normal, hyperplastic and neoplastic salivary tissue was analysed to see whether activation of the angiogenic process is essential in salivary gland carcinogenesis. Immunostaining with anti-endothelial cells (anti-CD31), anti-beta3 integrin and anti-laminin antibodies revealed that microvessel density was significantly higher in normal and hyperplastic than in neoplastic tissue, in which no signs of new vessel sprouting were found. Assessment of angiogenic factor expression indicates a low presence of VEGF in normal, hyperplastic and neoplastic epithelium, while bFGF was preferentially produced but not exported by neoplastic cells and remained in a cell-associated form. Our data suggest that normal salivary gland vascularization is able to support tumor onset and development with no need for an angiogenic switch.