Helper T-cell Phenotype Research Articles

Prognostic Significance of CD30 Expression and Response to Brentuximab Vedotin in Patients with Angioimmunoblastic T Cell Lymphoma

Background Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) characterized by a follicular helper T-cell phenotype. The standard frontline treatment for AITL typically involves CHOP or CHOP-like regimens, with consideration for autologous stem cell transplant. A promising treatment option for CD30-positive (CD30+) PTCLs, including AITL, is the anti-CD30 antibody drug conjugate, brentuximab vedotin (BV). The ECHELON-2 study demonstrated equivocal outcomes in CD30+ PTCL patients (pts) who received BV-CHP instead of CHOP. However, response of BV in CD30+ AITL pts is still uncertain. This study aims to evaluate the relationship between CD30 expression and the clinical response to BV in pts diagnosed with AITL. Methods This retrospective IRB approved study conducted at MD Anderson Cancer Center, where we analyzed pts with AITL diagnosed between 1997- 2023. Patient demographics, laboratory data at diagnosis, pathology review, treatment, and treatment response were collected and analyzed. Expression of CD30 expression in neoplastic cells was evaluated by immunohistochemistry and scored in 5% increments. Kaplan- Meier method was used to assess overall survival (OS) and log-rank used to compare different groups. Results This study included a cohort of 339 pts with AITL. Among them, 55 (23%, n=237) had no detectable CD30 expression (CD30=0%),182 (77%, n=237) patients had detectable CD30 expression (CD30>1%), and 102 pts had unknown CD30 expression. Table 1 shows patient characteristics by CD30 expression and response to first-, second-, and third- line BV treatment. There were 113 (48%, n=237) females and 124 (52%, n=237) males with a median age of 66 years. Most patients were Whites (88%, n=196) followed by Black (4%, n=196), and Asian (5%, n=196). Fifty-two (n=122) of pts who were CD30+ had stage III, 43% (n=122) had stage IV (p-value= <0.001), and 38% had BM involvement (p- value= 0.3). For pts with disease showing no CD30 expression (CD30neg) 16% (n=43) of pts had stage III, 70% (n=43) had stage IV, and 48% (n=42) had BM involvement. Auto-Stem cell transplant (ASCT) was performed in 48% of those with CD30+ and 43% of CD30neg. The most common first-line treatment was chemotherapy combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by other CHOP like regimens. In total, 35 pts received BV treatment as first-line, 32 patients received BV in combination with chemotherapy and 3 received BV only. For second-line treatment, 11 received BV treatment and for third- line only 6 received BV. First- line treatment with BV showed better clinical response rates, with 82% achieving complete response (CR, n= 34), followed by second line CR with 56% (n= 9) and third- line with 0% (n= 6). The median OS were similar between those with CD30+ who did or did not receive first line BV (20 months vs. 19 months, p>0.05). The median OS for CD30neg pts who did not receive BV was 25 months (p=0.42). Furthermore, there was no statistically significant difference in OS between pts who underwent a ASCT (CD30+ 24.5 months and CD30neg 32.5 months, respectively) and those who did not (CD30+ 18.5 months and CD30neg 24.5 months, respectively, p- value = 0.29). Conclusion While this study did not find CD30 expression to be a predictor of response to BV treatment or ASCT in AITL pts, it provides valuable insights into the prevalence of CD30 expression and BV response as first- line treatment. Notably, 77% of pts had CD30 expression and pts who received BV as first- line had a higher proportion of CRs compared to pts who received BV as second- and third- line treatments. Further investigations with larger patient cohorts are necessary to determine the prognostic and predictive role of CD30 in AITL. Additional studies analyzing CD30 expression levels in malignant cells, immunoblasts, and macrophages are planned for presentation at the upcoming annual meeting.

Dual epigenetic therapy in TET2 gene positive extranodal peripheral T-cell lymphoma with follicular helper T-cell (TFH) phenotype: a case report and literature review

Dual epigenetic therapy in TET2 gene positive extranodal peripheral T-cell lymphoma with follicular helper T-cell (TFH) phenotype: a case report and literature review

Distinct and overlapping features of nodal peripheral T-cell lymphomas exhibiting a follicular helper T-cell phenotype: a multicenter study emphasizing the clinicopathological significance of follicular helper T-cell marker expression

Nodal peripheral T-cell lymphoma (PTCL) is a heterogeneous category including angioimmunoblastic T-cell lymphoma (AITL), PTCL of follicular helper T-cell (Tfh) phenotype (PTCL-Tfh), and PTCL, not otherwise specified (PTCL-NOS). We explored Tfh marker profiles in nodal PTCL. Nodal PTCLs (n=129) were reclassified into AITL (58%; 75/129), PTCL-Tfh (26%; 34/129), and PTCL-NOS (16%; 20/129). Histologically, clear cell clusters, high endothelial venules, follicular dendritic cell proliferation, EBV+cells, and Hodgkin-Reed-Sternberg (HRS)-like cells were more common in AITL than PTCL-Tfh (HRS-like cells, P=.005; otherwise, P<.001) and PTCL-NOS (HRS-like cells, P=.028; otherwise, P<.001). PTCL-NOS had a higher Ki-67 index than AITL (P=.001) and PTCL-Tfh (P=.002). Clinically, AITL had frequent B symptoms (versus PTCL-Tfh, P=.010), while PTCL-NOS exhibited low stage (versus AITL+PTCL-Tfh, P=.036). Positive Tfh markers were greater in AITL (3.5±1.1) than PTCL-Tfh (2.9±0.9; P=.006) and PTCL-NOS (0.5±0.5; P<.001). Tfh markers showed close correlations among them and AITL-defining histology. By clustering analysis, AITL and PTCL-NOS were relatively exclusively clustered, while PTCL-Tfh overlapped with them. Survival was not different among the PTCL entities. By Cox regression, sex and ECOG performance status (PS) independently predicted shorter progression-free survival in the whole cohort (male, P=.001, HR=2.5; PS≥2, P=.010, HR=1.9) and in 'Tfh-lymphomas' (ie, AITL+PTCL-Tfh) (male, P=.001, HR=2.6; PS≥2, P=.016, HR=2.1), while only PS predicted shorter overall survival (OS) in the whole cohort (P=.012, HR=2.7) and in 'Tfh-lymphomas' (P=.001; HR=3.2). ICOS predicted favorable OS in 'Tfh-lymphomas' (log-rank; P=.016). Despite the overlapping features, nodal PTCL entities could be characterized by Tfh markers revealing clinicopathologic implications.

Primary Extranodal Follicular T-Cell Lymphoma and Ductal Breast Carcinoma Diagnosed by a Magnetic Resonance Imaging-Guided Vacuum-Assisted Biopsy: A Case Report

Patient: Female, 62-year-oldFinal Diagnosis: Primary non-Hodgkin lymphoma and ductal carcinoma in-situSymptoms: No specific symptomsMedication:—Clinical Procedure: —Specialty: RadiologyObjective:Rare co-existance of disease or pathologyBackground:Extranodal non-Hodgkin’s lymphomas (NHLs) are most commonly low-grade B-cell lymphomas, and the breast is not an usual site for this condition. This case report describes a 62-year-old woman with a primary NHL and ductal carcinoma in situ (DCIS) of the left breast diagnosed by a magnetic resonance imaging (MRI)-guided vacuum-assisted breast biopsy. The simultaneous diagnosis of breast cancer and NHL is rare, with few cases described in the literature. Primary breast lymphomas account only for 0.04% to 0.5% of breast malignancies.Case Report:In November 2016, a 62-year-old woman was treated for a peripheral T-cell lymphoma (follicular helper T-cell phenotype) of the left upper central breast; later she underwent periodic breast imaging follow-ups. In October 2018, MRI revealed a focal 33-mm non-mass contrast enhancement (according to the Breast Imaging Reporting and Data System –MRI lexicon of the American College of Radiology) in the lower external quadrant of the left breast. Neither mammography nor ultrasonography demonstrated any suspicious features. The multidisciplinary medical team performed an MRI-guided vacuum-assisted breast biopsy and the histological analysis confirmed the diagnosis of a DCIS. Subsequently, she underwent surgery resulting in eradication of the disease and has had regular follow-ups, including mammography, ultrasonography, and MRI.Conclusions:This is a rare case of both a primary NHL of the breast and DCIS, which was detected only by MRI. It highlights the role of an MRI-guided vacuum-assisted breast biopsy, which allows an accurate and economic diagnosis in case of suspicious findings on MRI. We recommend the use of MRI in follow-ups for patients with previous breast lymphomas (high-risk patients).

Mycosis fungoides in Taiwan shows a relatively high frequency of large cell transformation and CD56 expression

Mycosis fungoides (MF) is an indolent cutaneous T-cell lymphoma and may transform into large cell lymphoma in the disease course. The incidence of MF in Taiwan is lower as compared to that in the West. In this study we aimed to characterise the clinicopathological, immunohistochemical, and genetic features of transformed MF (t-MF) in Taiwan. We retrospectively collected MF cases from April 2004 to April 2015 from four medical centres in Taiwan, reviewed the clinical history and histopathology, and performed immunohistochemistry, in situ hybridisation for EBV (EBER), and fluorescence in situ hybridisation (FISH) for DUSP22/MUM1 gene translocation. Fifty-one specimens from 32 patients with MF were identified with a male to female ratio of 1.5:1 and a median age of 50.5 (range 16-82). Tumours from 11 patients (34%) underwent large cell transformation, with the median age at 61 (range 26-82). The tumour cells of t-MF expressed CD30 and MUM1 in 82% and 100% cases, respectively. CD56 was expressed in two (10%) of 21 MF cases and two (18%) of 11 t-MF cases, respectively; and all four CD56-positive cases were of a helper T-cell phenotype. All CD56 expressing MF and t-MF tumours tested for EBER were negative. FISH study showed rearranged DUSP22/IRF4 in one (9%) of 11 t-MF cases, but not in any of the 19 non-transformed MF specimens. Four patients with t-MF died of disease and six were alive with disease in a median follow-up time of 25 months (mean 44.7 months). Large cell transformation and aberrant CD56 expression were more frequent in patients with MF in Taiwan compared to those in the West. Larger case series and/or national studies are needed to clarify the significance and impact of large cell transformation on the prognosis of patients with MF.

Using molecular chemokine adjuvants to target the germinal center reaction and enhance HIV-specific humoral responses to DNA immunogens in the mucosa or the periphery

Abstract The germinal center (GC) is a dynamic cellular substructure found in lymphoid organs where follicular helper T cells (TFH) provide the necessary proliferation stimuli and cytokine signaling that promote antibody classs-witching and affinity maturation of B cell receptors. DNA vaccines have demonstrated great potential as vaccine immunogens and in vivo electroporation (EP) has enhanced this immunogenicity. The ability to deliver plasmid encoded molecular adjuvants to direct immune responses is an advantage of the DNA platform. Mucosa-associated epithelial chemokine (MEC, or CCL28) is secreted by epithelial cells that line mucosal surfaces, it signals through CC-chemokine receptors 10 and 3 (CCR10 and CCR3) which are expressed on IgA+ plasma cells, TH17 cells, and mucosa-resident antigen presenting cells. IL-12 is a T cell stimulating cytokine that promotes a helper-T cell phenotype. Mice were vaccinated twice intramuscularly with either consensus HIV-1 env DNA alone or DNA plus molecular MEC or IL-12 delivered by in vivo EP. Fourteen days post vaccination, animals were sacrificed and spleens and draining lymph nodes were harvested for flow cytometric analysis. Both MEC and IL-12 significantly increased antigen-specific GC B cells (B220+CD138−Igm−IgD−PNA+CXCR5+gp120+) (11.1% and 8.91% respectively, compared to 6% with DNA alone). Antigen specific isotype- ELISA confirmed that MEC increases IgA in serum (900ng/ml compare to 600ng/ml with DNA alone) and fecal extracts (27ng/ml compared to 22ng/ml), while IL-12 increases IgG in serum alone (2200ng/ml compared to 1300ng/ml with DNA alone). These data indicate that molecular adjuvants can be used to specifically direct immune responses to the mucosa or the periphery.

Differential NFATc1 Expression in Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoma and Other Forms of Cutaneous T-Cell Lymphoma and Pseudolymphoma.

Primary cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (PCSTCL) has recently emerged as a distinct clinicopathological entity. Because of a considerable degree of overlap with pseudolymphoma, the diagnosis is often challenging. Preliminary studies suggest that nuclear upregulation of calcineurin/nuclear factor of activated T cells (NFAT) may play a role in lymphomagenesis. 137 cases (70 males and 67 female, mean age = 55) of various forms of cutaneous T-cell and B-cell infiltration were evaluated for NFATc1 expression. The study comprised 18 cases of PCSTCL, 45 cases of mycosis fungoides (MF), 5 cases of lymphomatoid papulosis (LyP), 5 cases of anaplastic large-cell lymphoma (ALCL), 8 cases of other forms of peripheral T-cell lymphoma, not otherwise specified, 12 precursor lesions of MF (ie, cutaneous T-cell dyscrasias), 35 cases of pseudolymphomas, 8 primary cutaneous B-cell lymphoma, and 1 chronic lymphocytic leukemia. The number of cells exhibiting a nuclear stain was counted per 10 high-power field and 2-tailed statistical analysis was used for comparison of nuclear NFATc1 expression between primary PCSTCL and all other groups. A P-value <0.05 was considered to indicate statistical significance. All cases of PCSTCL showed nuclear staining for NFATc1 (mean = 296 ± 236) with no cases in which an exclusive cytoplasmic stain was observed. The cells exhibiting this staining pattern were oftentimes larger manifesting other features of a follicular helper T-cell phenotype, such as variable positivity for PD1, ICOS, CXCL13, and BCL6. In comparison, an exclusively cytoplasmic stain was observed in 29 cases of MF; in few cases, rare nuclear staining cells were observed averaging less than 10 per high-power field (P = 0.0001). These positive staining cases were not only limited to tumor-stage MF but also encompassed patch- and plaque-stage lesions and follicular variants of MF. The same pattern was observed in cases of T-cell dyscrasia (mean = 3 ± 3, P = 0.0001) and pseudolymphoma (mean = 2 ± 3, P = 0.0001), both revealing a dominant cytoplasmic staining pattern. In pseudolymphomatous folliculitis, a greater extent of nuclear staining for NFATc1 was observed compared with other forms of pseudolymphoma. No significant difference was seen between MF and T-cell dyscrasia or pesudolymphomas excluding pseudolymphotous folliculitis. Anaplastic large-cell lymphoma cases showed an almost exclusive cytoplasmic staining pattern with rare nuclear staining (mean = 55 ± 102, P = 0.0001); similar results were observed in LyP (mean = 17 ± 15, P = 0.004). Cutaneous B-cell lymphomas showed a similar extent of staining as that noted for PCSTCL. The greatest extent of staining was observed in chronic lymphocytic leukemia. A significant difference was noted between the extent of nuclear staining in PCSTCL and other forms of primary cutaneous T-cell lymphoma, type unspecified (mean = 22 ± 43, P = 0.0002), although not between PCSTCL and B-cell lymphoma. NFAT signaling plays a critical role in peripheral T-cell activation after T cell receptor engagement. When assessing T-cell-rich infiltrates where the differential diagnosis is largely between a PCSTCL and pseudolymphoma, a significant degree of nuclear staining of lymphocytes would be more in keeping with a diagnosis of PCSTCL. Upregulation of the NFAT pathway is not a feature of tumor progression in the setting of MF.

Clonal identity and histologic difference in peripheral T-cell lymphoma with follicular helper T-cell phenotype simultaneously occurring at common bile duct and lymph nodes

We present the first case of peripheral T-cell lymphoma, not otherwise specified expressing follicular helper T-cell markers with different histologic features simultaneously involving the common bile duct and pericholedochal lymph nodes in a 72-year-old woman patient. Abdominal computed tomography revealed a localized wall thickening in the common bile duct. With the impression of cholangiocarcinoma, pancreaticoduodenectomy was done. Microscopically, dense small lymphoid cells with only minimal cytologic atypia were observed with occasional lymphoepithelial-like lesions, whereas many atypical large cells infiltrated the pericholedochal lymph nodes. Immunohistochemically, most small cells in the bile duct and the large atypical cells in the lymph nodes were all reactive for follicular helper T-cell markers including CD4, PD-1, and CXCL-13. BIOMED-2 based polymerase chain reaction using the DNA template from either the bile duct lesion or the lymph node revealed identical but different dominant clonal peaks, indicating these 2 lesions represent a spectrum of the same disease.

Synergy Of Small-Molecule Inhibitors In Cutaneous T-Cell Lymphoma Cells: A Discovery Tool To Define New Therapeutic Targets In T-Cell Receptor (TCR) Signaling Pathways

Cutaneous T-Cell Lymphomas (CTCL) represent a heterogeneous group of hematopoietic malignancies that account for 5-10% of Non-Hodgkin Lymphomas. The initial disease presentation is characterized by the infiltration of the skin by malignant clonal CD4+ lymphocytes that possess a mature memory helper T-cell phenotype. CTCL patients present in a spectrum of defined disease phenotypes, Mycosis Fungoides (MF) and Sézary Syndrome (SS) being the most common. Thus, it is not surprising that no underlying molecular basis for disease has been identified. Standard treatment protocols are designed to provide palliation, as no chemotherapeutic compound(s) has demonstrated increased long-term or disease-free survival. Currently, no curative therapy for CTCL exists. Our long-term goal is to gain a better understanding of the pathways governing CTCL cell survival and proliferation while identifying druggable targets for the development of new and more effective therapeutics.The principles of chemical biology, to discover and elucidate molecular pathways fundamental in cellular, developmental, and disease biology through synthetic organic chemistry, are readily applied to the field drug discovery. Using these methods, we have previously observed that inhibition of protein kinase C (PKC) β with the small molecule Enzastaurin (Enz), combined with inhibition of glycogen synthase kinase 3 (GSK3) with AR-A014418 (ARA), causes synergistic apoptosis in CTCL cell lines (Hut78 and H9) and patient cells. Further investigations have shown combined treatment with Enz and ARA increased β-catenin protein levels and that β-catenin downstream transcription activation negatively impacts CTCL viability. However, β-catenin alone is not sufficient to induce CTCL apoptosis. These data indicate there are additional mechanisms of cell death stimulated by the combined inhibition of PKC and GSK3.To identify the β-catenin independent targets of combined PKC and GSK3 inhibition, we have assayed drug-treatment induced changes in global gene expression through a microarray approach. We have identified transcripts that are significantly regulated after combined inhibition of PKC and GSK3 with Enz, ARA, and a combination of both small molecules. We are focusing our efforts on those targets and signaling pathways that are minimally regulated by each drug alone (or no change at all), but are dramatically impacted by the combination treatment to identify mechanisms of synergy. Using Gene Set Enrichment Analysis (GSEA), we noted enrichment in two pathways that are key to T-cell viability, namely the T-cell receptor (TCR) pathway and interferon response pathway. To elucidate candidate genes that may have therapeutic importance and to further explore the clinical relevance of our data set, in a pilot study, we interrogated the gene expression profile of a set of CTCL patients normalized to normal CD4+ T-cells. We then selected those genes whose expression is negatively correlated between CTCL patients and drug treated CTCL cell lines. From this pilot study, we have identified members of the TCR pathway that are over-expressed in CTCL patients and strikingly down-regulated by combined inhibition of PKC and GSK3. Taken together, these observations prompted us to further explore genes of the TCR signaling cascade as potential therapeutic targets. These data will provide the basis for downstream target identification for further drug development. Disclosures:No relevant conflicts of interest to declare.

Relapsed angioimmunoblastic T-cell lymphoma with acquired expression of CD20: a case report and review of the literature

BackgroundAngioimmunoblastic T-cell lymphoma is one of the most common types of peripheral T-cell lymphomas, usually presenting at an older age with an aggressive clinical course. Its characteristic morphological presentation and follicular helper T-cell phenotype help to distinguish it from other T-cell lymphomas.Case presentationWe recently encountered the unique case of a 63-year old patient with relapsed tumour-cell rich angioimmunoblastic T-cell lymphoma, presenting with a “classical” phenotype and, in addition, an acquired, strong, aberrant expression of CD20.“Lineage infidelity” of phenotypic markers is a well-documented phenomenon in lymphomas and leukemias, a circumstance currently still poorly understood and with the potential to bring about erroneous interpretations, causing diagnostic havoc. This case represents one of the few documented angioimmunoblastic T-cell lymphomas with strong CD20 expression. Of interest, CD20 expression was only detected in the recurrent lymphoma and not upon initial diagnosis. The clinical importance of this finding lies in the potential for treatment with an anti-CD20 antibody, for instance Rituximab, in addition to standard chemotherapy protocols for angioimmunoblastic T-cell lymphoma.ConclusionDiagnostic work-up of lymphomas to determine their lineage should therefore consider morphology, pheno- as well as genotypic characteristics, where appropriate, and in particular signs of progression and change in marker profile in relapsed cases e.g. acquisition of “non-lineage” markers such as CD20 in T-cell lymphoma.

Abstract B14: Synergy of small-molecule inhibitors in cutaneous T-cell lymphoma cells: A discovery tool to define new therapeutic targets

Abstract Cutaneous T-Cell Lymphomas (CTCL) represent a heterogeneous group of hematopoietic malignancies that account for 5-10% of Non-Hodgkin Lymphomas. The initial disease presentation is characterized by the infiltration of the skin by malignant clonal CD4+ lymphocytes that possess a mature memory helper T-cell phenotype. CTCL patients present in a spectrum of defined disease phenotypes, Mycosis Fungoides (MF) and Sézary Syndrome (SS) being the most common. Thus, it is not surprising that no underlying molecular basis for disease has been identified. Standard treatment protocols are designed to provide palliation, as no chemotherapeutic compound(s) has demonstrated increased long-term or disease-free survival. Currently, no curative therapy for CTCL exists. Our long-term goal is to gain a better understanding of the pathways governing CTCL cell survival and proliferation while identifying druggable targets for the development of new and more effective therapeutics. The principles of chemical biology, to discover and elucidate molecular pathways fundamental in cellular, developmental, and disease biology through synthetic organic chemistry, are readily applied to the field drug discovery. Using these methods, we have previously observed that inhibition of protein kinase C (PKC) β with the small molecule Enzastaurin (Enz), combined with inhibition of glycogen synthase kinase 3 (GSK3) with AR-A014418 (ARA), causes synergistic apoptosis in CTCL cell lines (Hut78 and H9). Critically, this cell death is dependent on the increase in active β-catenin protein expression. Treatment of cells with ICAT, a protein that prevents the interaction of β-catenin and TCF, demonstrated that β-catenin-mediated transcriptional activity participates in the combined compound—induced cell death. In order to assess potential targets of Enz and ARA treatment, we recently screened downstream β-catenin-mediated targets with a commercially available signaling pathway PCR array and validated them with qRT-PCR. Several targets of β-catenin were differentially regulated by the combined small-molecule treatment. We decreased cellular β-catenin by either siRNA knockdown or shRNA in stable cell lines and determined that β-catenin is required for compound-induced cytotoxicity of CTCL cell lines. In contrast, overexpression of β-catenin in CTCL cell lines demonstrated β-catenin alone is not sufficient to induce apoptosis. Thus, while we have identified β-catenin as a key regulator of CTCL viability, there are likely additional undescribed mechanisms of cell death stimulated by the combined inhibition of PKC and GSK3. From these data, we conclude that the combined inhibition of PKC and GSK signaling in CTCL causes cell death by impacting β-catenin specific targets as well as by stimulating cell death independent of β-catenin. To further elucidate these mechanisms we are assaying drug-treatment induced changes in global gene expression through a microarray approach. We are identifying transcripts that are significantly regulated after combined inhibition of PKC and GSK3 with Enz and ARA respectively. These data will provide the basis for downstream target identification for further drug development. Citation Format: Meghan Bliss-Moreau, Weimin Xiao, Preethi Gunaratne, Nancy L. Krett, Steven T. Rosen. Synergy of small-molecule inhibitors in cutaneous T-cell lymphoma cells: A discovery tool to define new therapeutic targets. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B14.

Cutaneous T Cell Lymphoma in Skin Folds with a Follicular Helper T-Cell Phenotype

A subset of cutaneous T-cell lymphomas (CTCLs) may derive from a recently described subset of helper T cells called follicular helper T cells. These cells help to recruit B cells and induce them to mature and differentiate. Tumors arising from these cells have a signature phenotype (positive for CXCR5 and its ligands). …

Expression of Master Regulators of Helper T-Cell Differentiation in Peripheral T-Cell Lymphoma, Not Otherwise Specified, by Immunohistochemical Analysis

The normal counterparts of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have not been accurately identified. We immunohistochemically analyzed 10 PTCL-NOS cases to examine the expression of the master regulators of T-cell differentiation and of surface antigens, including chemokine receptors. All cases were positive for the master regulator of helper T cells (Th-POK) and the marker of effector T cells (CD45RO). Three cases each were positive for T-Bet and GATA3, which are master regulators of helper T cells (T(H) ) type 1 (T(H)1) and 2 (T(H)2), respectively. Two cases were positive for the surface antigens of central memory (Tcm) (CCR7 and CD62L), and 1 case was positive for follicular helper T-cell (TFH) phenotype (BCL6, CXCL13, and PD-1). The remaining case was negative for all markers of effector T(H) subtypes. These results suggest the postulated normal counterparts of PTCL-NOS identified in 9 of the 10 cases consist of T(H)1, T(H)2, TCM, and TFH.

Expression of Master Regulators of Helper T-Cell Differentiation in Peripheral T-Cell Lymphoma, Not Otherwise Specified by Immunohistochemical Analysis.

Abstract 5004 BackgroundPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) comprises nodal and extranodal mature T-cell lymphomas, which do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.During T-cell maturation, naïve T-cells include two distinct cell types, CD4-positive helper T-cells (Th) and CD8-positive cytotoxic T-cells. Following antigen stimulation, naïve Th cells differentiate into several subtypes of effector Th cells, including helper T-cells type1 (Th1), helper T-cells type 2 (Th2), follicular helper T-cells (TFH), regulatory T-cells (Treg), IL-17 producing T-cells (Th17), central memory T-cells (TCM), and effector memory T-cells (TEM).Previously, these subtypes of effector Th cells have been classified according to their pattern of cytokine secretion and expression of surface antigens, including chemokine receptors. More recent immunological researches have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with Th, Th1, Th2, Th17, and Treg differentiation are reported to be Th-POK, T-Bet, GATA3, RORγt, and FOXP3, respectively.The origin of the neoplastic cells of PTCL-NOS is thought to be effector Th cells because the tumor cells usually express specific surface antigens such as pan-T-cell markers (CD2 and CD3), an effector T-cell marker (CD45RO), and a Th marker (CD4). However, the normal cellular derivation of PTCL-NOS remains unclear because the immunophenotypic profiles of PTCL-NOS are heterogeneous and not entirely disease specific.To presume the normal counterparts of PTCL-NOS, we used immunohistochemical analysis to examine the expression of the master regulators of T-cell differentiation and surface antigens, including chemokine receptors associated with the subtypes of Th cells. Patients and MethodsThe study population included ten Japanese patients who were diagnosed histopathologically with PTCL-NOS at the hospital of Kyoto Prefectural University of Medicine from 1993 to 2008. There were six male and four female patients who ranged in age from 26 to 78 years (mean 56 years) at diagnosis.Immunohistochemical staining was applied to 4-μm-thick paraffin-embedded sections of diagnostic lymph node, skin or liver tumor biopsy specimens. Sections were stained using a standard indirect avidin-biotin horseradish peroxidase method and diaminobenzidine (DAB) color development. Cases were considered positive if 25% or more of the tumor cells were stained with an antibody. For negative and positive staining controls, we used paraffin-embedded tissue sections of tonsillitis, nonspecific lymphadenitis, AILT, follicular lymphoma and diffuse large B-cell lymphoma. ResultsFirst, we examined the expression of the master regulator of helper T-cells (Th-POK) and the marker of effector T-cells (CD45RO), and all cases were positive for both.Next, we examined the expression of the master regulators of differentiation to subpopulations within Th cells (Th1, Th2, Treg and Th17). Three cases each were positive for T-Bet, and GATA3, but none of the cases showed FOXP3 or RORγt.Among the four cases not expressing these master regulators, two cases were positive for the surface antigens of central memory (TCM) (CCR7 and CD62L), and one case was positive for follicular helper T-cell (TFH) phenotype (BCL6, CXCL13 and PD-1). The remaining case was negative for all markers of effector Th subtypes. ConclusionsAll ten PTCL-NOS cases exhibited CD45RO and Th-POK, which characterized effector helper T-cells. Furthermore, the lymphoma cells of nine of the ten cases exhibited the expression of master regulators or surface antigens which characterized Th1, Th2, TCM and TFH. DisclosuresNo relevant conflicts of interest to declare.

The role of chemokines and cytokines in lung fibrosis

Idiopathic pulmonary fibrosis (IPF) exhibits a complex and poorly understood pathogenesis. Overt inflammation in the lungs of patients with established IPF is absent, and classic anti-inflammatory therapies are inefficacious; however, inflammation may contribute to the disruption of the normal alveolar architecture, allowing interaction between fibroblasts and the epithelium. The polarisation of the inflammatory response toward a type-2 helper T-cell phenotype may also be important in the development of pulmonary fibrosis, as fibroproliferation could be favoured over repair. Furthermore, evidence has emerged regarding an imbalance between angiogenic and angiostatic chemokine levels, leading to an overall angiogenic pattern of expression in both animal models and tissue specimens from IPF patients. The precise role of vascular remodelling in IPF remains to be determined. Therefore, numerous questions exist regarding the role and importance of chemokines and cytokines in pulmonary fibrosis. Further investigation is required to facilitate the elucidation of IPF pathogenesis and identification of novel targets for treatment of this dismal disease.

Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice.

Helper T (Th) cells are classified as Th1 or Th2 cells by virtue of cytokine secretion and function as mediators of cellular or humoral immunity, respectively. Cytokines also regulate the differentiation of Th cells. For example, interleukin (IL)-12 promotes Th1 and suppresses Th2 cell development, suggesting that IL-12 may be useful therapeutically in Th2-mediated autoimmune and allergic disorders. Therefore, the effect of systemic IL-12 treatment on in vivo autoantibody synthesis in hepatitis B e antigen (HBeAg)-expressing transgenic mice, which is dependent on self-reactive Th2 cells, was examined. Low-dose IL-12 significantly inhibited autoantibody production by shifting the Th2-mediated response toward Th1 predominance. Additionally, previous studies suggest that a predominance of HBeAg-specific Th2-type cells may contribute to chronicity in hepatitis B virus infection. Therefore, IL-12 may also prove beneficial in modulating the HBeAg-specific Th response to favor viral clearance in chronic hepatitis B virus infection.

Immunologic type of thyroid lymphoma in an adult T-cell leukemia endemic area in Japan.

Our previous study showed that thyroid non-Hodgkin's lymphoma (TL) in an adult T-cell leukemia/lymphoma (ATL) non-endemic area were exclusively B-cell derived. The present study was carried out to examine whether TL in an ATL endemic area are also exclusively of B-cell type. Eight cases with TL admitted to the hospital situated in an ATL endemic area were studied: they were all female with an age range from 50 to 75 (median 67) years. Histologically four of the eight cases showed a follicular pattern. Immunophenotypic study revealed all but one case to be of B-cell nature: CD3-, 4-, 8-, 20+, 22+, 45RA+, 45RO-, L22-, L24+/-, L28+. Neoplastic cells in one case with the histology of diffuse large cell lymphoma showed a CD3+, 4+, 8-, 20-, 22-, 45RA-, 45RO+/-, L22-, L24-, L28-, indicating a helper T-cell phenotype. Genotypic study showed rearrangement of T-cell beta-chain receptor in this case. This case also had antibodies against HTLV-1 in the serum. This case shows that it is also possible to develop T-cell TL in an endemic ATL area.

Review of Systemic Therapy for Cutaneous T-Cell Lymphomas

The cutaneous T-cell lymphomas (CTCL) mycosis fungoides and Sezary's syndrome are low-grade, non-Hodgkin lymphomas with a mature helper T-cell phenotype that always have a cutaneous component. Systemic involvement occurs early in disease, often before it is evident clinically. Systemic therapy is frequently used to treat CTCL, but there has been a longstanding de-bate as to whether early aggressive systemic therapy is warranted. In this …

Multiple karyotypic abnormalities in three cases of small cell variant of T-cell prolymphocytic leukemia

Cytogenetic, clinical, and laboratory findings of three patients with a small cell variant of T-cell prolymphocytic leukemia (T-PLL) are presented. Immunophenotypic studies of the morphologically typical small cell variant prolymphocytes showed a mature helper T-cell phenotype (CD4 + CD8 −) in one patient and a common thymocyte phenotype (CD4 + CD8 −) in two other patients. The cytogenetic analysis revealed complex karyotypes with several structural aberrations in the peripheral blood lymphocytes of all three patients. In all cases chromosome 14 was affected with the breakpoint at 14q11. Inversion (14) and isochromosome 8q, often reported as an additional aberration in T-PLL, were detected in two of the patients. In two patients a translocation of the short arm of chromosome 12 was also seen. The T-cell receptor β-chain gene showed a clonal rearrangement in all three patients, whereas no rearrangements were detected in the immunoglobulin genes. The survival of the patients ranged from 10 weeks to 48 months. The association between cytogenetic, clinical, and laboratory data is discussed.

A Clonal CD4-Positive T-Cell Line Established from the Blood of a Patient with Sézary Syndrome

The reported inability to establish long-term T-cell lines from the blood of cutaneous T-cell lymphoma patients with circulating neoplastic T cells has hindered the development of an in vitro system to investigate Sézary syndrome. We have established a rapidly proliferating T-cell line from the peripheral blood of a patient with Sézary syndrome, which expresses a mature helper T-cell phenotype and contains cytogenetic abnormalities and T-cell receptor gene rearrangements identical to those in the patient's blood. The method of establishment and characteristics of this line are described.