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Background To understand humoral responses elicited after xenotransplantation, we compared the induction of anti-non-Gal antibodies vs. anti-Gal antibodies in non-human primates (NHPs) after intraportal porcine islet transplantation (PITX). Methods Anti-Gal and anti-non-Gal IgGs were analyzed in serial plasma samples of NHP recipients after PITX by enzyme-linked immunosorbent assay (ELISA) using synthetic Gal and by flow cytometry using α-1,3-galactosyltransferase gene knockout (GTKO) porcine endothelial cells, respectively. Anti-non-Gal IgG was detected in some recipients after PITX. The specificity of anti-non-Gal IgG was investigated by two-dimensional electrophoresis of the protein extract from GTKO porcine endothelial cells, Western blot analysis of recipient pre- and post-PITX plasma, and MALDI-TOF/TOF mass spectrometry, revealing albumin, a non-glycosylated protein in the serum supplement of the islets solution, as a putative antigen for anti-non-Gal IgG. The binding of IgG antibodies to human albumin (HA), bovine albumin (BA), porcine albumin (PA), and Gal was compared by ELISA in pre- and post-PITX plasma samples of 30 NHP recipients subjected to intraportal PITX, which were grouped according to the use of CD40-CD154 blockade and sirolimus. Results One of the immunoblot-matched spots was identified as BA by mass spectrometry. By ELISA, the plasma used in the immunoblot analysis revealed strong IgG binding to BA and PA, but not to HA. Anti-PA, anti-BA, and anti-Gal antibodies in NHP recipients 1 month after PITX were detected in 5 (100%), 3 (60%), and 5 (100%), respectively, of the 5 recipients receiving various immunosuppression (IS) without CD40-CD154 blockade (group I) and in 0 (0%), 0 (0%), and 4 (16%), respectively, of the 25 recipients receiving IS with CD40-CD154 blockade and sirolimus (group II). This finding revealed significant differences between the groups (P

Recently, a novel CD4(+) T-cell developmental pathway was reported that generates thymocyte-thymocyte (T-T) CD4(+) T cells. We established a mouse system (CIITA(tg)CIITApIV(-/-)) where thymic positive selection occurred only by major histocompatibility complex (MHC) class II(+) thymocytes. T-T CD4(+) T cells selected via MHC class II-dependent T-T interaction are comprised of PLZF-negative and innate PLZF-positive populations. Until recently, the functional role of the PLZF-negative population was unclear. In this study, we demonstrate that naïve T-T CD4(+) T cells provide B-cell help to a level comparable with that of naïve conventional CD4(+) T cells. Considering the absence of PLZF expression in naïve T-T CD4(+) T cells, these results suggest that PLZF-negative naïve T-T CD4(+) T cells are functionally equivalent to conventional naïve CD4(+) T cells in terms of B-cell help.

Unlike conventional T cells, innate-like T cells such as natural killer (NK) T cells are selected by homotypic T-cell interactions. Recently, a few reports have shown that T-T CD4(+) T cells can be generated in a similar manner to that for NKT cells. These two types of cells share common functional properties such as rapid response to antigenic encounters and the potential for a panoply of cytokine secretion. However, T-T CD4(+) T cells differ from NKT cells in that they are restricted by highly polymorphic major histocompatibility complex (MHC) II molecules and have a diverse T-cell receptor repertoire. Additional example of T-T interactions was recently reported in which peripheral T cells re-circulate to the thymus and participate in the thymocyte selection process. In this review, we dissect the cellular mechanisms underlying the production of T-T CD4(+) and NKT cells, with particular emphasis on the differences between these two T-cell prototypes. Finally, we propose that T-T CD4(+) T cells serve two major functions: one as an acute-phase reactant against viral infection and the other is the generation of anti-ergotypic CD4(+) T cells for regulatory purposes. All of these features make it possible to create a diverse set of functional cells through MHC class II-restricted T-T interactions.

Despite considerable progress over the last decade, Hodgkin lymphoma (HL) remains a malignant tumor of unknown pathogenesis. The role of Epstein-Barr virus (EBV) and the activation of transcription factor NF-κB have been noted in the tumorigenesis of classic HL. Recently, a distinctive interaction between CD99 and the EBV viral latent membrane protein 1 (LMP1) was observed in the process of the malignant transformation of EBV-infected B cells. It was previously reported that CD99 expression is negatively regulated by LMP1, subsequently generating cells with Hodgkin and Reed-Sternberg (HRS) cell phenotype. Interestingly, several pieces of evidence have been recently revealed the presence of mutual regulation between CD99 and LMP1, which may assist in determining HL pathogenesis. In this review, the roles of CD99 and LMP1 in the generation of the HRS cell, a tumor cell of HL, will be discussed. We also suggest that CD99 and LMP1 interaction in an in vivo system may provide new insight into the understanding of the molecular mechanism of HL.

Papillary thyroid cancers often occur as multiple foci. Multifocal cancers have been considered to have a poor prognosis because they are thought to be the consequence of intrathyroidal spread of the papillary cancer. However, to the authors' knowledge there has been little investigation into whether multifocal thyroid papillary carcinomas arise from the intrathyroidal spread of a single carcinoma or from independent primary tumors. To answer this question, the BRAF(V600E) mutational status of individual tumor foci was examined. This approach was justified because in the Korean population a high proportion (65%) of papillary carcinomas harbor the BRAF mutation.DNA was isolated from paraffin-embedded tissue samples of multifocal papillary thyroid carcinoma and the BRAF exon 15 was amplified by the polymerase chain reaction (PCR). The PCR product was digested with restriction endonuclease TspRI to test for the presence of the BRAF(V600E) (T1799A) mutation.In all, 140 cancers from 61 patients diagnosed with multifocal papillary carcinoma were examined. The BRAF mutation was found in all the individual cancers in 29 (47.5%) of the patients (all-positive group) and the mutation was absent in all the individual cancers in 8 (13.1%) patients (all-negative group). However, in 24 (39.3%) patients, some of the individual cancers contained the BRAF mutation, whereas others did not (mixed group).At least 39.3% of the multifocal papillary cancers in the Korean population that were examined could be attributed to independently arising papillary cancers rather than to intrathyroidal spread of single cancers.

We studied the role of lipid rafts and actin cytoskeleton in CD99-mediated signaling to elucidate the mechanism of protein transport upon CD99 engagement. CD99 engagement in Jurkat cells elicited the exocytic transport of GM1 as well as several surface molecules closely related with CD99 functions. In addition, CD99 molecules were rapidly incorporated into lipid rafts and appeared to rearrange the actin cytoskeleton upon CD99 stimulation. Association of CD99 with actin cytoskeleton was inhibited by methyl-β-cyclodextrin, while CD99-mediated GM1 clustering was inhibited by cytochalasin D. Therefore, we suggest that CD99 may play a role in the vesicular transport of transmembrane proteins and lipid rafts from the intracellular location to the cell surface, possibly by effecting actin cytoskeleton reorganization.

The authors describe a case of idiopathic hypereosinophilic syndrome (HES) terminated as a T-cell lymphoma in a 3-year-old girl. The clinical course was chronic and characterized by chronic eczema, persistent peripheral blood eosinophilia, organomegaly, interstitial lung change, and pericarditis. Postmortem examination demonstrated a disseminated T-cell lymphoma involving the inguinal lymph node, liver, lung, and kidney. The findings of the current case suggest a possibility that certain abnormalities in this case of idiopathic HES per se may have triggered the development of malignant lymphoma, and it may represent a transition of idiopathic HES into a T-cell lymphoma. Other possible sequences are discussed. The development of T-cell malignancy in idiopathic HES in a girl is quite an unusual presentation.