Common pathological findings in the heart in COVID-19-related sudden death cases: An autopsy case series.

Background: Cardiomyopathy is a leading cause of sudden out-of-hospital death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination. Such unexpected COVID-19-related cardiomyopathies are challenging to diagnose as specific pathological findings are not always identified. Case summary: We reported the autopsy findings of two cases of sudden death due to COVID-19-related cardiomyopathies. In one case, death occurred after SARS-CoV-2 infection, while in the other, after COVID-19 vaccination. We found common pathological findings in both hearts: decreased staining intensity with special stains, loss of rhabdomeres, and multivacuolation in cardiomyocytes without inflammatory cell infiltration. The remaining organs showed no findings that could have contributed to the deaths. Conclusion: In cases of sudden death after SARS-CoV-2 infection or COVID-19 vaccination, the decreased staining intensity with special stains may aid the diagnosis of sudden death due to COVID-19-related cardiomyopathy, even when H&E staining shows few findings.

[A supratentorial primitive neuroectodermal tumor exhibiting pathological characteristics of medulloepithelioma: a case report].

A 50-year-old female presented with headache symptoms and left hemifacial paresis. Brain computed tomography and magnetic resonance images demonstrated a right frontal lobe tumor with hemorrhage and calcification. A gross total resection was carried out. Pathologically, the tumor exhibited three kinds of structures. The first was an astrocytic area which occupied the large part of this tumor. Small, round cells, which were positive for glial fibrillary acidic protein, were randomly distributed. The second was an epithelioid area with the highest MIB-1 labeling index of the three structures. Undifferentiated tumor cells demonstrated a dense proliferation, and short spindle-shaped cells exhibited an epithelial and a partly luminal alignment that resembled the embryonal neural tube. The third was a sarcomatoid area. Long spindle-shaped cells, which were positive for vimentin, were in a bundle-like form. We diagnosed this tumor as a primitive neuroectodermal tumor (PNET) with epithelial differentiation. PNETs are rare brain tumors with a predominance in children. Histologically, undifferentiated tumor cells demonstrate dense proliferations. The tumor arises from germinal matrix cells that differentiate into neuronal, glial, and ependymal cells. Medulloepithelioma, which is classified in the PNET category, is a very rare brain tumor that usually develops in childhood. Pathological studies have demonstrated that papillary, tubular, or trabecular arrangements of neoplastic neuroepithelium mimic the embryonic neural tube predominantly. In our case, the tumor partly demonstrated epithelial differentiation, which is a feature of medulloepithelioma, not only glial and mesenchymal differentiation. This is a rare case of PNET with uncommon histological features.

siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft-versus-host disease.

Acute graft-versus-host disease (aGvHD) remains a major threat to a successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Although antibody-based targeting of the CD40/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T-cell costimulatory pathway. Here, we used small interfering RNA (siRNA) complexed with ß-glucan allowing the binding and uptake of the siRNA/ß-glucan complex (siCD40/schizophyllan [SPG]; chemical modifications called NJA-312, NJA-302, and NJA-515) into Dectin1+ cells, which recognize this pathogen-associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40/SPG, NJA-312, and NJA-302 ameliorated aGvHD-mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA-312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA-312 treatment caused delayed initial donor T and B-cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA-312 reduced organ damage by suppressing CCR2+, F4/80+, and IL17A-expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP-recognizing lectin Dectin1 changes the immunological niche, suppresses organ-specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue-specific immune reactions using Pathogen-associated molecular pattern (PAMP) molecules like 1,3-ß-glucan for cell delivery of siRNA.

Six-transmembrane epithelial antigen of the prostate and enhancer of zeste homolog 2 as immunotherapeutic targets for lung cancer.

BACKGROUND: T-cell based immunotherapy for lung cancer (LC) could be a promising and novel therapeutic approach. Six-transmembrane epithelial antigen of the prostate (STEAP) and the polycomb group protein enhancer of zeste homolog 2 (EZH2) are highly expressed in LC and since the expression of molecules in normal tissue is significantly lower as compared to tumor cells, these proteins are considered as potential tumor-associated antigens (TAAs) for developing T-cell based immunotherapy. METHODS: We assessed the capacity of predicted CD4 T-cell epitopes from STEAP and EZH2 to induce anti-tumor immune responses to LC cell lines. RESULTS: Out of several predicted epitopes, two synthetic peptides, STEAP281-296 and EZH295-109, were effective in inducing CD4 T-cell responses that were restricted by HLA-DR1, DR15, or DR53 molecules, indicating that the peptides function as promiscuous T-cell epitopes. Moreover, STEAP281-296 and EZH295-109-reactive T-cells could directly recognize STEAP or EZH2 expressing LC cells in an HLA-DR restricted manner. In addition, some STEAP-reactive T-cells responded to STEAP+ tumor cell lysates presented by autologous dendric cells. Most significantly, both of these peptides were capable of stimulating in vitro T-cell responses in patients with LC. CONCLUSIONS: Peptides STEAP281-296 and EZH295-109 function as strong CD4 T-cell epitopes that can elicit effective anti-tumor T-cell responses against STEAP or EZH2 expressing LC. These observations may facilitate the translation of T-cell based immunotherapy into the clinic for the treatment of LC.

Characterization of human CD4 helper T cell responses against Aurora kinase A.

Aurora kinase A (Aurora-A) is a cell cycle-associated serine-threonine kinase that is overexpressed by various types of cancer and is highly associated with poor prognosis. Since the expression of Aurora-A in normal tissues has been shown to be significantly lower as compared to tumor cells, this protein is being considered as a potential tumor-associated antigen for developing immunotherapies. The goal in the present study was to identify CD4 helper T lymphocyte (HTL) epitopes for Aurora-A for the design of T cell-based immunotherapies against Aurora-A-expressing tumors. Synthetic peptides corresponding to potential HTL epitopes were identified from Aurora-A and used to stimulate CD4 T lymphocytes in vitro to generate antigen-specific HTL clones that were evaluated for antigen specificity, MHC restriction and for their ability to interact with Aurora-A-expressing tumor cells. The results show that two peptides (Aurora-A(161-175) and Aurora-A(233-247)) were effective in generating HTL responses that were restricted by more than one MHC class II allele (i.e., promiscuous responses). The CD4 HTL clones were able to directly recognize Aurora-A-expressing tumor cells in an antigen-specific and MHC class II-restricted manner and some of the clones displayed cytolytic activity toward Aurora-A + tumor cells. Both of these peptides were capable of stimulating in vitro T cell responses in patients with bladder cancer.

Six-transmembrane epithelial antigen of the prostate as an immunotherapeutic target for renal cell and bladder cancer.

PURPOSE: T-cell based immunotherapy for renal cell and bladder cancer is one of the most promising therapeutic approaches. STEAP is a novel cell surface protein that is over expressed in various cancers, including renal cell and bladder cancer. Recently we induced STEAP specific helper T lymphocytes that recognize the naturally processed STEAP peptide epitopes STEAP(102-116) and STEAP(192-206) arising from STEAP expressing tumor cells. Thus, STEAP may be a useful tumor associated antigen for designing T-cell based immunotherapy. We determined whether STEAP could induce anti-cellular immune responses to urological cancer. MATERIALS AND METHODS: We selected 2 previously described STEAP derived epitope peptides, STEAP(102-116) and STEAP(192-206), and examined their ability to elicit helper T-lymphocyte responses by in vitro vaccination of CD4 T lymphocytes from healthy individuals and patients with cancer. RESULTS: STEAP peptides induced helper T-lymphocyte responses using lymphocytes from healthy individuals that directly recognized STEAP expressing, DR positive renal cell and bladder cancer cells, and autologous dendritic cells pulsed with STEAP expressing tumor cell lysates in a major histocompatibility complex class II restricted manner. These peptides also stimulated T-cell responses in patients with renal cell or bladder cancer. Each STEAP peptides behaved as a promiscuous T-cell epitope, in that they stimulated T cells in the context of multiple major histocompatibility complex class II alleles. CONCLUSIONS: Results show that STEAP helper T-lymphocyte epitopes could be used to optimize T-cell based immunotherapy against STEAP expressing renal cell and bladder cancer.

Focal adhesion kinase as an immunotherapeutic target.

BACKGROUND: Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune cellular responses. METHODS: To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients. RESULTS: Two synthetic peptides, FAK(143-157) and FAK(1,000-1,014), induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient's CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients. CONCLUSIONS: Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors.

Recognition of prostate and melanoma tumor cells by six-transmembrane epithelial antigen of prostate-specific helper T lymphocytes in a human leukocyte antigen class II-restricted manner.

The six-transmembrane epithelial antigen of prostate (STEAP) protein is an attractive candidate for T cell-based immunotherapy because it is overexpressed in prostate cancer and various other tumor types. Several peptide epitopes capable of stimulating CTLs that killed STEAP-expressing tumor cells have been described. Our goal was the identification of helper T lymphocyte (HTL) epitopes of STEAP for the optimization of T cell-based immunotherapies against STEAP-expressing malignancies. Candidate HTL epitopes for STEAP were predicted using in silico algorithms for HLA class II-binding peptides and were tested for their ability to elicit HTL responses by in vitro peptide vaccination of CD4 T lymphocytes from healthy individuals and prostate cancer patients. Two peptides (STEAP(102-116) and STEAP(192-206)) were effective in stimulating in vitro antitumor HTL responses in both normal individuals and prostate cancer patients. Notably, both STEAP HTL peptides behaved as promiscuous T-cell epitopes because they stimulated T cells in the context of more than one MHC class II allele. These newly described STEAP HTL epitopes could be of value for the design and optimization of T cell-based immunotherapy against STEAP-expressing tumors.

Gastrointestinal manifestation of immunoglobulin G4-related disease: clarification through a multicenter survey.

BACKGROUND: Several reports on immunoglobulin (Ig)G4-related disease (IgG4-RD) with gastrointestinal involvement (IgG4-related gastrointestinal disease; IgG4-GID) have been published, although this entity has not been fully established clinicopathologically. Thus, we carried out a multicenter survey. METHODS: Patients with possible IgG4-GID who underwent resection were collected. Histologic slides were reevaluated, and eight cases with diffuse lymphoplasmacytic infiltration but without numerous neutrophils, granulations or epithelioid granulomas were further analyzed. RESULTS: Overall, the IgG4 counts (87-345/high-power field) and IgG4/IgG-positive ratio were high (44-115%). The demographic findings included advanced age among the patients (55-80 years) and male preponderance (six cases). Six lesions (five gastric, one esophageal), consisting of lymphoplasmacytic infiltration with neural involvement in the muscularis propria and/or bottom-heavy plasmacytosis in the gastric mucosa, were histologically regarded as highly suggestive of IgG4-RD. Storiform fibrosis and obliterative phlebitis were found in two cases, and the former gave rise to a 7-cm-sized inflammatory pseudotumor (IPT) in one case. Ulceration and carcinoma co-existed in three and two lesions, respectively. All the patients had other organ involvement (OOI), and serum IgG4 levels were markedly elevated (four of five patients). The remaining two cases with gastric IPTs featuring reactive nodular fibrous pseudotumor or nodular lymphoid hyperplasia were regarded as possible cases of IgG4-RD because of the histologic findings and lack of OOI. CONCLUSIONS: IgG4-GID is found in the setting of IgG4-RD, often with ulceration or cancer. Characteristic histologic findings are observed in the muscularis propria and gastric mucosa. Cases with IPT may be heterogeneous, and there may be mimickers of IgG4-GID.

In vitro peptide immunization of target tax protein human T-cell leukemia virus type 1-specific CD4+ helper T lymphocytes.

PURPOSE: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1 Tax is the most dominant antigen for HTLV-1-specific CD8(+) CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4(+) helper T lymphocytes in HTLV-1 Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II-restricted epitopes that could be used for vaccine development. EXPERIMENTAL DESIGN: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4(+) T lymphocytes. RESULTS: Peptides Tax(191-205) and Tax(305-319) were effective in inducing T-helper-cell responses. Although Tax(191-205) was restricted by the HLA-DR1 and DR9 alleles, responses to Tax(305-319) were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1(+) T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1 Tax(+) tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide-based vaccine capable of inducing simultaneous CTL and T-helper responses. CONCLUSION: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4(+) helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.

Recognition of prostate and breast tumor cells by helper T lymphocytes specific for a prostate and breast tumor-associated antigen, TARP.

PURPOSE: T cell-based immunotherapy via the in vitro or in vivo expansion of prostate tumor-associated antigen (TAA)-specific T lymphocytes is one of the most promising therapeutic approaches to treat prostate cancer. T-cell alternate reading frame protein (TARP) is a mitochondrial protein that is specifically expressed in prostate epithelial cells. We have done experiments aimed at identifying helper T lymphocyte (HTL) epitopes for TARP for the design of T cell-based immunotherapy for prostate cancer. EXPERIMENTAL DESIGN: Dendritic cells from normal donors were pulsed with synthetic peptides derived from TARP, which were predicted to serve as HTL epitopes. These dendritic cells were used to stimulate CD4(+) T cells in vitro to trigger HTL responses against TARP. T-cell responses to these peptides were also studied with lymphocytes from prostate cancer patients. RESULTS: The two peptides, TARP(1-14) and TARP(14-27), were shown to elicit effective in vitro HTL responses using lymphocytes from both normal volunteers and prostate cancer patients. Peptide TARP(1-14)-reactive HTLs were found restricted by HLA-DR53 and could recognize naturally processed protein antigen derived from tumor cells, which was presented by autologous dendritic cells. Most significantly, stimulation with peptide TARP(14-27) generated four HTL lines restricted by HLA-DR1, HLA-DR9, HLA-DR13, and HLA-DR15, some of which capable of recognizing naturally processed antigens presented by dendritic cell or directly by TARP-positive tumor cells. CONCLUSIONS: Our results show that TARP constitutes a TAA that can be recognized by tumor-reactive HTL. The newly described TARP epitopes could be used to optimize and improve T-cell epitope-based immunotherapy against prostate and other tumors expressing TARP.

Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients.

PURPOSE: Nasal natural killer (NK)/T-cell lymphoma is associated with EBV and has distinct clinical and histologic features. However, little is known about its genetic features. In this study, we examined the genes expressed by SNK-6 and SNT-8 cells, which were established from nasal NK/T-cell lymphomas, and found that interleukin (IL)-9 was specifically expressed in these two cell lines. EXPERIMENTAL DESIGN: cDNA array was used to examine the genes expressed by SNK-6 and SNT-8 cells. Expression of IL-9 and IL-9 receptor was investigated by reverse transcription-PCR, ELISA, and flow cytometry. Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunohistologic staining and ELISA were used to examine IL-9 expression in biopsies and sera from patients, respectively. RESULTS: In cDNA array, expression of IL-9 mRNA was much higher in SNK-6 and SNT-8 cells than in NK-92 cells from non-nasal NK-cell lymphoma and peripheral blood mononuclear cells from healthy volunteers. Furthermore, IL-9 was specifically expressed by SNK-6 and SNT-8 cells but not by other NK-cell, NK-like T-cell, and T-cell lymphoma/leukemia cell lines. IL-9 receptor was also expressed on the surfaces of SNK-6 and SNT-8 cells. An IL-9-neutralizing antibody inhibited the growth of these two cell lines, whereas recombinant human IL-9 enhanced their growth. Most significantly, IL-9 was present in biopsies and sera from patients with this lymphoma. CONCLUSIONS: These results suggest that IL-9 plays an important role in nasal NK/T-cell lymphoma possibly via an autocrine mechanism.

Role of IGFBP7 in Diabetic Nephropathy: TGF-ß1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells.

Tubular injury is one of the important determinants of progressive renal failure in diabetic nephropathy (DN), and TGF-ß1 has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. The aim of this study was to identify novel therapeutic target molecules that play a role in the tubule damage of DN. We used an LC-MS/MS-based proteomic technique and human renal proximal epithelial cells (HRPTECs). Urine samples from Japanese patients with type 2 diabetes (n = 46) were used to quantify the candidate protein. Several proteins in HRPTECs in cultured media were observed to be driven by TGF-ß1, one of which was 33-kDa IGFBP7, which is a member of IGFBP family. TGF-ß1 up-regulated the expressions of IGFBP7 mRNA and protein in a dose- and time-dependent fashion via Smad2 and 4, but not MAPK pathways in HRPTECs. In addition, the knockdown of IGFBP7 restored the TGF-ß1-induced epithelial to mesenchymal transition (EMT). In the immunohistochemical analysis, IGFBP7 was localized to the cytoplasm of tubular cells but not that of glomerular cells in diabetic kidney. Urinary IGFBP7 levels were significantly higher in the patients with macroalbuminuria and were correlated with age (r = 0.308, p = 0.037), eGFR (r = -0.376, p = 0.01), urinary ß2-microglobulin (r = 0.385, p = 0.008), and urinary N-acetyl-beta-D-glucosaminidase (NAG) (r = 0.502, p = 0.000). A multivariate regression analysis identified urinary NAG and age as determinants associated with urinary IGFBP7 levels. In conclusion, our data suggest that TGF-ß1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-ß1-induced tubular injury in DN.

Integrally calcified solitary fibrous tumor in the retroperitoneum: a case report and review of the literature.

Solitary fibrous tumor (SFT) is a rare stromal neoplasm and usually occurs in the thoracic cavity. We here report a case of retroperitoneal SFT with prominent calcification. A 64-year-old man presented with an incidentally detected retroperitoneal mass in the right upper abdomen. Imaging tests indicated an integrally calcified mass. The lesion was observed for 2 years and laparoscopically resected according to the patient's wish. Microscopically, the mass was mostly occupied by calcification and proliferous spindle cells were scattered with positive CD34 expression. We diagnosed morphologically benign SFT and the patient remained disease-free 1 year after the excision. There has been no report of such integrally calcified SFT. Retroperitoneal SFT is difficult to make a preoperative diagnosis, and careful follow-up after the excision is recommended because morphological malignancy does not always correspond to clinical malignancy.

Visinin-Like Protein-3 Modulates the Interaction Between Cytochrome b 5 and NADH-Cytochrome b 5 Reductase in a Ca2+-Dependent Manner.

Visinin-like proteins (VILIPs) belong to the calcium sensor protein family. VILIP-1 has been examined as a cerebrospinal fluid biomarker and as a potential indicator for cognitive decline in Alzheimer's disease (AD). However, little is known about VILIP-3 protein biochemistry. We performed co-immunoprecipitation experiments to examine whether VILIP-3 can interact with reduced nicotine adenine dinucleotide (NADH)-cytochrome b 5 reductase. We also evaluated the specificity of cytochrome b 5 within the visinin-like protein subfamily and identified cytochrome P450 isoforms in the brain. In this study, we show that cytochrome b 5 has an affinity for hippocalcin, neurocalcin-δ, and VILIP-3, but not visinin-like protein-1. VILIP-3 was also shown to interact with NADH-cytochrome b 5 reductase in a Ca2+-dependent manner. These results suggest that VILIP-3, hippocalcin, and neurocalcin-δ provide a Ca2+-dependent modulation to the NADH-dependent microsomal electron transport. The results also suggest that future therapeutic strategies that target calcium-signaling pathways and VILIPs may be of value.

CD56/NCAM-positive Langerhans cell sarcoma: a clinicopathologic study of 4 cases.

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100beta, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

Identification of naturally processed helper T-cell epitopes from prostate-specific membrane antigen using peptide-based in vitro stimulation.

PURPOSE: There is growing evidence that CD4(+) helper T lymphocytes (HTLs) play an essential role in the induction and long-term maintenance of antitumor CTL responses. Thus, approaches to develop effective T-cell-based immunotherapy should focus in the stimulation of both CTLs and HTLs reactive against tumor-associated antigens. The present studies were performed with the purpose of identifying HTL epitopes for prostate-specific membrane antigen (PSMA) for the optimization of vaccines for prostate cancer. EXPERIMENTAL DESIGN: Synthetic peptides from regions of the PSMA sequence that were predicted to serve as HTL epitopes were prepared with use of computer-based algorithms and tested for their capacity to trigger in vitro HTL responses in lymphocytes from normal volunteers. RESULTS: Our results show that 4 peptides from PSMA were effective in eliciting HTL responses. Moreover, HTL reactive to 3 of the 4 peptides were capable of reacting with naturally processed antigen in the form of freeze/thaw lysates or apoptotic cells produced from PSMA-positive LNCaP tumor cell lines. CONCLUSIONS: Human HTLs are capable of effectively recognizing epitopes derived from PSMA. The information presented here should facilitate the design of improved vaccination strategies for prostate cancer.

Recognition of adult T-cell leukemia/lymphoma cells by CD4+ helper T lymphocytes specific for human T-cell leukemia virus type I envelope protein.

PURPOSE: Human T-cell leukemia virus type I (HTLV-I) can cause an adult T-cell leukemia/lymphoma (ATLL). Because ATLL is a life-threatening lymphoproliferative disorder and is resistant to chemotherapy, the establishment and enhancement of T-cell immunity to HTLV-I through the development of therapeutic vaccines could be of value. Thus, the identification of HTLV-I epitopes for both CD8(+) and CD4(+) T cells should facilitate the development of effective vaccines. Although numerous HTLV-I epitopes for CTLs have been identified, few epitopes recognized by CD4(+) helper T cells against this virus have been described. EXPERIMENTAL DESIGN: Synthetic peptides prepared from several regions of the HTLV-I envelope (Env) sequence that were predicted to serve as helper T-cell epitopes were prepared with use of computer-based algorithms and tested for their capacity to trigger in vitro helper T-cell responses using lymphocytes from normal volunteers. RESULTS: The results show that the HTLV-I-Env(317-331), and HTLV-I-Env(384-398)-reactive helper T lymphocytes restricted by HLA-DQw6 and HLA-DR15, respectively, could recognize intact HTLV-I+ T-cell lymphoma cells and, as a consequence, secrete lymphokines. In addition, HTLV-I Env(196-210)-reactive helper T lymphocytes restricted by HLA-DR9 were able to directly kill HTLV-I+ lymphoma cells and recognize naturally processed antigen derived from killed HTLV-I+ lymphoma cells, which was presented to the helper T cells by autologous antigen-presenting cells. CONCLUSIONS: The present findings hold relevance for the design and optimization of T-cell epitope-based immunotherapy against HTLV-I-induced diseases such as ATLL.

Spontaneous hemorrhage from splenic tissue 13 years after total splenectomy: report of a case.

A 33-year-old man suffered sudden abdominal distension without traumatic episodes. He had undergone total splenectomy for hereditary spherocytosis 13 years ago. He was in shock, and his hemoglobin level was 10.5 g/dl. Contrast enhanced computed tomography revealed a giant mass in the left upper abdomen and extravasation of the contrast material into the mass. Excision of the mass was performed, and microscopic examination showed a giant hematoma surrounded by normal splenic tissue. We speculated that an accessory spleen or splenosis had enlarged for the 13 years and ruptured. The patient remained asymptomatic 4 months after the surgery. Spontaneous hemorrhage from accessory spleens or splenosis is extremely rare, and relevant case reports suggest that surgical resection of bleeding sites yields favorable prognosis although preoperative qualitative diagnosis seems to be difficult.