Low Expression Of HLA Class Research Articles

Comparison of Autologous and Allogeneic Adipose-Derived Stem Cells in Kidney Transplantation: Immunological Considerations and Therapeutic Efficacy.

Regenerative medicine shows significant potential in treating kidney diseases through the application of various types of stem and progenitor cells, including mesenchymal stem cells (MSCs), renal stem/progenitor cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Stem cells possess the unique ability to repair injured organs and improve impaired functions, making them a key element in the research of therapies for kidney tissue repair and organ regeneration. In kidney transplantation, reperfusion injury can cause tissue destruction, leading to an initially low glomerular filtration rate and long-term impact on function by creating irreversible interstitial fibrosis. MSCs have proven useful in repairing early tissue injury in animal models of kidney, lung, heart, and intestine transplantation. The use of stem cell therapies in solid organ transplantation raises the question of whether autologous or allogeneic cells should be preferred. Adipose-derived stem cells (ASCs), characterized by the lack of HLA Class II molecules and low expression of HLA Class I and co-stimulatory signals, are considered immune-privileged. However, the actual risk of graft rejection associated with allogeneic ASCs remains unclear. It has been demonstrated that donor-derived ASCs can promote the development of Treg cells in vitro, and some degree of tolerance induction has been observed in vivo. Nevertheless, a study comparing the efficacy of autologous and allogeneic ASCs in a rat model with a total MHC mismatch for kidney transplantation showed that donor-derived administration of ASCs did not improve the grafts' survival and was associated with increased mortality through an immunologically mediated mechanism. Given the lack of data, autologous ASCs appear to be a safer option in this research context. The aim of this review was to examine the differences between autologous and allogeneic ASCs in the context of their application in kidney transplantation therapies, considering potential immune reactions and therapeutic efficacy. Some have argued that ASCs harvested from end-stage renal disease (ESRD) patients may have lower regenerative potential due to the toxic effects of uremia, potentially limiting their use in transplantation settings. However, evidence suggests that the beneficial properties of ASCs are not affected by uremia or dialysis. Indeed, some investigators have demonstrated that ASCs harvested from chronic kidney disease (CKD) patients exhibit normal characteristics and function, maintaining consistent proliferative capacity and genetic stability over time, even after prolonged exposure to uremic serum Furthermore, no differences were observed in the response of ASCs to immune activation or their inhibitory effect on the proliferation of alloantigen-activated peripheral blood mononuclear cells between patients with normal or impaired renal function. This review presents the current achievements in stem cell research aimed at treating kidney diseases, highlighting significant progress and ongoing efforts in the development of stem cell-based therapies. Despite the encouraging results, further research is needed to overcome the current limitations and fully realize the potential of these innovative treatments. Advances in this field are crucial for developing effective therapies that can address the complex challenges associated with kidney damage and failure.

Impact of HLA-B Dimorphism in the Leader Peptide on Clinical Outcome in AML

NK cells are negatively regulated by inhibitory receptors, such as the family of Killer Immunoglobulin-like Receptors (KIR) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules, and recent studies suggest that an HLA-B dimorphism in the leader peptide at position -21 dictates whether NK cell regulation mainly relies on the KIRs or the NKG2A/CD94 receptor. Thus, haplotypes with -21M delivers functional peptides to HLA-E, but will rarely harbor genes encoding the KIR ligand HLA-C2. However, little is known regarding the clinical implications of this dimorphism. For this study, we performed HLA typing and an extensive flow cytometry analysis of the NK cell repertoire in 80 AML patients who received immunotherapy with histamine dihydrochloride (HDC) and IL-2 for the prevention of relapse in the post-consolidation phase. Below median levels of HLA class I expression, reflecting low-grade NK cell inhibition, were found to correlate with significantly better outcome in HDC/IL-2-treated patients, indicating that the efficacy of the immunotherapy is NK cell-dependent. In contrast to healthy controls, the majority of NK cells in AML patients in complete remission displayed expression of NKG2A, which was even more prominent in patients after 3 weeks of HDC/IL-2 treatment, or after in vitro culture of NK cells with IL-2. Thirty-eight patients (47.5 %) carried the M/x genotype in HLA B -21 (predicting NKG2A dependence) and 42 patients (52.5 %) carried the T/T genotype (KIR dependence). Despite the high percentage of NKG2A+ NK cells, M/x patients showed significantly improved leukemia-free survival (p=0.04) and overall survival (p=0.007) compared with T/T patients. Only patients with M/x genotype benefited from low expression of HLA class I. The IL-2-induced NKG2A expression was associated with enhanced NKG2A-mediated inhibition as pure populations of NKG2A-expressing NK cells were inhibited by a leukemic cell line transfected to express the NKG2A ligand HLA E, which was reverted by antibody blockade of NKG2A. Our results suggest that the outcome of AML immunotherapy is affected by (i) expression levels of HLA class I, and (ii) the HLA B-21 dimorphism and, hence, whether the KIR or NKG2A-CD94 are the dominant inhibitory pathway for NK cells. Furthermore, the pronounced expression of NKG2A in HDC/IL-2-treated patients suggests that combination strategies, including checkpoint inhibitors targeting NKG2A together with HDC/IL-2, may be feasible for relapse prevention in AML. DisclosuresBrune:Novartis: Other: reimbursement for lecture. Aurelius:Immune Pharmaceuticals: Patents & Royalties: Pending patent protecting the use of NOX2 inhibitors in cancer. Martner:Immune Pharmaceuticals: Patents & Royalties: Pending patent protecting the use of NOX2 inhibitors in cancer. Hellstrand:Immune Pharmaceuticals: Patents & Royalties: Filed or pending patents protecting the use of NOX2 inhibitors in cancer. Thoren:Immune Pharmaceuticals: Patents & Royalties: Pending patent protecting the use of NOX2 inhibitors in cancer.

Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies.

The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.

The prognostic landscape of genes and infiltrating immune cells in cytokine induced killer cell treated-lung squamous cell carcinoma and adenocarcinoma.

Objective:Patients with non–small cell lung cancer (NSCLC) respond differently to cytokine-induced killer cell (CIK) treatment. Therefore, potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated. The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital. We performed whole-exome sequencing (WES) on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC, and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment. Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance. WES and RNA-seq data between lung squamous cell carcinoma (SCC) and adenocarcinoma (Aden) were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS, as analyzed by multivariate Cox proportional hazard regression (P = 0.031). The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment. Relatively low expression of HLA class II genes and checkpoint molecules, and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules, as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.

Ex Vivo Expanded NK Cells Mediate Highly Efficient and Rapid Killing of Ewing Sarcoma Cells Through Degranulation with Tumor Cytotoxicity Controlled by the NKG2D, DNAM-1, and NKp30 NK Receptors

Introduction: Natural killer (NK) cells are highly cytotoxic immune cells that can kill tumor cells via release of cytotoxic granulae as well as through induction of tumor apoptosis by ligands that bind death receptors expressed on the target cells. Clinical trials have established that adoptive infusions of ex vivo expanded NK cells are safe and can induce tumor regression in selected groups of cancer patients. Recent data suggest that Ewing's sarcoma (EwS), a bone cancer associated with poor survival in the context of metastatic disease, is exquisitely sensitive to killing by NK cells due to low expression of HLA class I molecules that normally prevent NK cell cytotoxicity through interactions with inhibitory NK cell receptors. We and others have recently shown that ex vivo expansion of NK cells causes upregulation of their activation receptors such as NKG2D and death receptor ligands such as TRAIL, which collectively make expanded NK cells more cytotoxic than resting non-expanded NK cells. In an effort to optimize the full therapeutic potential of adoptive NK cell immunotherapy against EwS in the clinic, we investigated the mechanisms utilized by ex vivo expanded NK cells to recognize and kill EwS cells.Methods: Healthy donorNK cells were expanded for 14 days using irradiated EBV-LCL cells in X-Vivo 20 media supplemented with 500 IU/ml IL-2 and 10% AB serum. The EwS cell lines (TC71, RH18X, LG) and the K562 cell line were grown in RPMI media supplemented with 10% FBS. NK cell viability, phenotype, and degranulation were measured by flow cytometry. EwS lysis was measured using 51 Cr release assays. Degradation of perforin to prevent tumor killing via the degranulation pathway was achieved by pre-treating NK cells for 2 hours with 100 nM concanamycin. Blocking antibodies against HLA-A,B,C antigens on EwS cells and against activation receptors on NK cells were added to the respective cells for 30-45 min prior to co-culture. In some experiments, EwS cells were pre-treated with 20 nM bortezomib for 24 hours prior to co-culture with NK cells. Statistical analysis was conducted using the Wilcoxon ranked sum test to determine significance.Results: Ex vivo expanded NK cells were highly cytotoxic against all three EwS cell lines tested, with killing levels comparable to those of the gold-standard NK cell target K562 cells. Suppression of the degranulation pathway using concanamycin revealed a significant reduction in the ability of NK cells to lyse EwS cells (65-71% at baseline vs 10-24% with concanamycin-treated NK cells). Blockade of HLA class I molecules on the EwS cell surface revealed a small but significant increase in NK cell degranulation from 30 to 37%, 32 to 40%, and 20 to 35% against the TC71, RH18X, and LG EwS lines respectively (p <0.05). Based on experiments where individual activation receptors on ex vivo expanded NK cells were blocked with antibodies, we established that EwS killing by these cells was highly dependent on the expression of the NKG2D, DNAM-1, and NKp30 receptors. Although blockade of individual receptors significantly reduced NK cell killing of EwS cells, simultaneous blockade of all three receptors completely prevented NK cell degranulation. In an attempt to further bolster NK cell killing of EwS cells, we next pre-treated EwS cells with the proteasome inhibitor bortezomib to increase the expression of the TRAIL receptor DR5. While this approach increased DR5 expression by a median 2.09 fold (range 1.40-2.15) and enhanced the susceptibility of EwS cells to killing by recombinant TRAIL, surprisingly, no further killing was observed following co-culture with expanded NK cells. Preliminary data indicate the latter is explained by the rapid and efficient EwS killing induced by NK cell degranulation that triggers instant lysis in contrast to more delayed killing that is characteristic of the TRAIL pathways.Conclusions: Ex vivo expanded NK cells are able to rapidly and efficiently kill EwS cells at levels comparable to those of the gold-standard NK cell target K562 cells. Lysis of EwS by ex vivo expanded NK cells occurs exclusively through degranulation triggered by a relative lack of HLA class I expression combined with expression of ligands to the activating NK cell receptors NKG2D, DNAM-1, and NKp30. These data provide important insights that define the critical elements required by ex vivo expanded NK cells to mediate tumor responses against metastatic EwS following adoptive transfer in the clinic. DisclosuresNo relevant conflicts of interest to declare.

Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT).

Low expression of HLA class II antigens has been associated with more aggressive disease in several human malignancies including adult adrenocortical tumors (ACT), but their clinical relevance in pediatric ACT needs to be investigated. This study analyzed the expression profile of three class II histocompatibility genes (HLA-DRA, HLA-DPA1, and HLA-DPB1) in 58 consecutive pediatric ACT (13 adenomas and 45 carcinomas) by quantitative real time PCR and their association with clinical and biological features. HLA-DPA1 protein level was determined by immunohistochemistry. A significant association (P < 0.01) was observed between lower expression levels of the three genes analyzed and poor prognostic factors such as age ≥ 4 years, tumor size ≥ 200 cm(3), tumor weight ≥ 100 g, and metastatic disease; the presence of an unfavorable event and death. Underexpression of the HLA-DRA, HLA-DPA1, and HLA-DPB1 genes were associated with lower 5-year event-free survival (EFS) (P = 0.017, P < 0.001, and P = 0.017, respectively). Cox multivariate analysis showed that HLA-DPA1 was an independent prognostic factor (P = 0.029) when analyzed in association with stage IV, age and tumor size. Significantly lower EFS was also observed in patients with negative/weak immunostaining for HLA-DPA1 (P = 0.002). Similar results were observed when only patients classified as having carcinomas were analyzed. Our results suggest that lower expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 genes may contribute to more aggressive disease in pediatric ACT. HLA-DPA1 immunostaining may represent potential aggressiveness marker in this tumor.

Introduction of Tapasin Gene Restores Surface Expression of HLA Class I Molecules, but Not Antigen Presentation of an HIV Envelope Peptide in a Hepatoma Cell Line

A hepatoma cell line, Hep G2, reveals the diminished HLA class I surface expression and the reduced expression of LMP2, LMP7, and tapasin transcripts, suggesting that the reduced expression of these transcripts may be associated with the low expression of HLA class I molecules. Introduction of tapasin gene dramatically up-regulates the surface expression of HLA class I molecules on Hep G2 cells, and unexpectedly, enhances the expression of LMP2 and LMP7 transcripts as well. Unlike Hep G2, these tapasin-transfected Hep G2 cells are recognized by allo-specific CTL. However, the transfectant is unable to endogenously present an HIV envelope peptide to an HIV-specific CTL clone, suggesting that a proteasome-independent antigen processing pathway exists and still remains defective in the transfectant. These data may provide significant evidence that the nonproteasomal antigen processing pathway as well as the proteasomal pathway may be impaired in tumor cells to escape immune surveillance performed by CTL.

Circulating adhesion molecules (cICAM-1, lcVCAM-1) in patients with suspected inflammatory heart muscle disease

Some patients with non-ischemic heart failure show inflammatory changes in the myocardium which are thought to be of causal or pathogenetic relevance for the heart failure. The intercellular adhesion molecule-1 (ICAM-1) and the vascular adhesion molecule-1 (VCAM-1) are membrane proteins with receptor function from the immunoglobulin superfamily which mediate the vascular adhesion and transmigration of leucocytes into the tissue and undergo increased expression in chronic immunological-inflammatory processes. In addition to membrane-bound adhesion molecules, soluble forms can be detected in serum. In the present study we investigated the occurrence and the significance of circulating ICAM-1 and VCAM-1 in 71 patients with non-ischemic heart failure (47 M/24 F, mean age: 55 +/- 11 years). Serum concentrations of cICAM-1 and cVCAM-1 were analyzed using ELISA-Kits. The severity of heart failure was assessed in accordance to the NYHA-classification and to hemodynamic parameters (mean pulmonary pressure, left ventricular ejection fraction). Inflammatory heart disease was assessed histologically and immunohistologically (T-lymphocytes > 7.0/mm2, increased expression of the histocompatibility antigens of class I and II) in right ventricular endomyocardial biopsies. 16 healthy, age-matched patients (8 M/8 F, mean age: 55 +/- 6 years, mean ejection fraction 76 +/- 3%) without signs of inflammation in the myocardium (mean T-lymphocytes < 3.5 cells/mm2, low expression of HLA-class I and II) served as controls. The mean serum concentrations of circulating ICAM-1 and VCAM-1 (cICAM-1, cVCAM-1) were higher in patients with non-ischemic heart failure (372 +/- 107 ng/ml and 949 +/- 439 ng/ml) than controls (264 +/- 37 and 710 +/- 164 ng/ml) (p < 0.05). The mean concentrations of both adhesion molecules varied as a function of the mean pulmonary pressure and the left ventricular ejection fracture (for cICAM-1: Pearson's r: 0.24 and -0.33, p < 0.05; for cVCAM-1: Pearson's r: 0.28 and -0.26, p < 0.05). In 38% (n = 16) of patients with elevated concentrations of cICAM-1 (> or = 337 ng/ml) and 41% (n = 7) of those with elevated serum levels of cVCAM-1 (> or = 1038 ng/ml), the myocardial biopsies showed increased lymphocytic infiltration between 7 and 22 T-lymphocytes/mm2 and an enhanced expression of the MHC antigens of class I/II as sign of an activated inflammatory process in the myocardium. All patients with more than 9.3 T-lymphocytes/mm2 in the myocardium (n = 7) had higher serum levels of cICAM-1 (447 +/- 146 ng/ml, p < 0.05 compared to controls) and of cVCAM-1 (1577 +/- 688 ng/ml, p < 0.001). Both adhesion molecules correlated significantly with the mean number of T-lymphocytes in the myocardium (Pearson's r: 0.31-0.37, p < 0.05). The present study shows that the elevated levels of cICAM-1 and cVCAM-1 are often found in the serum of patients with non-ischemic heart failure. These raised serum levels correlate with inflammatory infiltrates in the myocardial tissue and with the clinical and hemodynamic signs of heart failure, thus, confirming a connection between heart failure and inflammatory changes in the myocardium.

Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome).

In this paper we describe the function and phenotype of natural killer (NK) lymphocytes from HLA class I-deficient patients. These cells are, as has been previously reported, unable to lyse HLA class I- K562 cells, but are able to perform antibody-dependent cellular cytotoxicity (ADCC), although with lower efficiency as compared to NK cells from normal individuals. Transporter associated to antigen processing (TAP)- NK cells proliferate when cultured in the presence of lymphoblastoid B cells (B-LCs) and interleukin 2 and develop a spectrum of cytotoxicity similar to that of activated normal NK cells. Importantly, activation of the TAP- NK cells induces strong cytotoxicity to autologous B-LCs. Analysis of the phenotype of circulating TAP- NK lymphocytes showed them to display a normal diverse repertoire of HLA class I-specific NK receptors. These receptors were expressed at normal levels, apart from the CD94-NKG2A complex, which appeared to be overexpressed. This latter finding could reflect an adaptation to the low expression of HLA class I molecules. Finally, functional analyses indicated that the inhibitory receptors in TAP- individuals can transduce inhibitory signals. Our results suggest that in vivo, the NK cells of TAP- patients could participate in immune defense, at least through ADCC, but upon activation, may be involved in autoimmune processes.

INVERSE CORRELATION BETWEEN EXPRESSION OF HLA‐B AND c‐myc IN UVEAL MELANOMA

HLA class I is expressed in 75–85 per cent of uveal melanoma and cytoplasmic c-myc expression has been reported in 78 per cent of uveal melanoma. In skin melanoma, an inverse relationship has been observed between HLA class I expression and c-myc. The purpose of this study was to determine whether a similar correlation occurred between high expression of c-myc and low expression of HLA class I in uveal melanoma. The expression of c-myc, HLA-A, and HLA-B was determined by immunohistochemistry on formalin-fixed and paraffin-embedded sections of 30 uveal melanomas. Cell cultures from four primary uveal melanomas (lines 92-1, MEL 202, OCM-1, and EOM-3) and one uveal melanoma metastasis (line OMM-1) were tested for mRNA levels of c-myc and HLA-A and HLA-B in Northern blot assays. The high level of expression of cytoplasmic c-myc was significantly correlated with low expression of HLA-B (P=0·03) and vice versa. High expression of HLA-B was significantly correlated with the presence of epithelioid cells (P=0·004). The inverse correlation observed between c-myc and HLA-B expression is similar to previous observations in cutaneous melanoma. By downregulating HLA-B expression, c-myc may influence the immune response in uveal melanoma. Tumours containing epithelioid cells showed a significantly higher expression of HLA-B than tumours of the spindle cell type. © 1997 by John Wiley & Sons, Ltd.

Inverse correlation between expression of HLA-B and c-myc in uveal melanoma.

HLA class I is expressed in 75-85 per cent of uveal melanoma and cytoplasmic c-myc expression has been reported in 78 per cent of uveal melanoma. In skin melanoma, an inverse relationship has been observed between HLA class I expression and c-myc. The purpose of this study was to determine whether a similar correlation occurred between high expression of c-myc and low expression of HLA class I in uveal melanoma. The expression of c-myc, HLA-A, and HLA-B was determined by immunohistochemistry on formalin-fixed and paraffin-embedded sections of 30 uveal melanomas. Cell cultures from four primary uveal melanomas (lines 92-1, MEL 202, OCM-1, and EOM-3) and one uveal melanoma metastasis (line OMM-1) were tested for mRNA levels of c-myc and HLA-A and HLA-B in Northern blot assays. The high level of expression of cytoplasmic c-myc was significantly correlated with low expression of HLA-B (P = 0.03) and vice versa. High expression of HLA-B was significantly correlated with the presence of epithelioid cells (P = 0.004). The inverse correlation observed between c-myc and HLA-B expression is similar to previous observations in cutaneous melanoma. By downregulating HLA-B expression, c-myc may influence the immune response in uveal melanoma. Tumours containing epithelioid cells showed a significantly higher expression of HLA-B than tumours of the spindle cell type.

Defective expression of HLA class I and CD1a molecules in boy with Marfan-like phenotype and deep skin ulcers

We report the case of a boy with low expression of HLA class I molecules on peripheral blood mononuclear cells, which is associated with immunodeficiency. The patient, who had a Marfan-like phenotype, had chronic deep skin ulcers and sinobronchiectasis. Immunohistologic examination of the ulcerated skin showed a dense perivascular infiltrate composed of normal mature lymphocytes and macrophages. All cells in the infiltrate showed an apparently normal expression of HLA class I molecules, but intraepidermal dendritic Langerhans' cells were negative for CD1a, an antigen that is a highly specific marker for these cells and is abundantly expressed in some self-healing forms of cutaneous lesions. It is therefore speculated that a defective expression of CD1a molecules can contribute to the chronic persistence of deep skin ulcers, which have already been reported in association with defective expression of HLA class I molecules.

HLA class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines

Antigenic marker expression was studied in a series of eight small cell lung carcinoma (SCLC) cell lines, according to their histological subtype, classic or variant. These lines were obtained from human tumors xenografted into nude mice, originally derived from heterotransplanted tumor biopsy samples. We looked at an altered expression of HLA class I antigens, a battery of neuroendocrine antigens and the P-glycoprotein (Pgp) responsible for MDR1 encoded multidrug resistance, as markers of tumor malignancy. Three cell lines out of four of the classic subtype and two cell lines out of four of the variant subtype showed a lack or a low expression of HLA class I antigen. Recombinant interferon gamma (rIFN-gamma) treatment (100 U/ml, for 48 h) increased HLA class I expression of the cell lines differently, but did not induce an imbalance between HLA-A and HLA-B molecules as described in other tumor models. Neuroendocrine antigens were tested in six out of these eight lines, using a family of monoclonal antibodies developed against the cell membrane antigens of low passage cell lines derived from pleural effusions (de Leij et al, Cancer Res 45: 2192-2200, 1985). Globally, these antigens were more highly expressed in classic subtypes of SCLC. Neuroendocrine antigens corresponding to MOC-21 and MOC-32 monoclonal antibodies were weakly expressed in variant forms. Pgp expression was detectable with the JSB1 monoclonal antibody on the three variant SCLCs out of the six lines. Comparing two cell lines originated from the same patient before and after therapy, we showed that neuroendocrine reactivity to MOC-21 and MOC-32 was lost simultaneously with a gain of Pgp expression, and with a classic to variant histological transition. With regard to the clinical evolution, HLA class I expression and stimulation by rIFN-gamma was not related to malignancy. It appears that for variant forms, a low expression of neuroendocrine antigens detected by MOC-21 and MOC-32 monoclonal antibodies and a high level of Pgp predict for a poor prognosis.

HLA antigens in colorectal tumours--low expression of HLA class I antigens in mucinous colorectal carcinomas.

Expression of HLA antigens and beta 2-microglobulin was studied by immunoperoxidase staining of frozen sections of 9 mucinous and 10 nonmucinous colorectal adenocarcinomas, 1 cloacogenic carcinoma, 12 colorectal adenomas and 4 samples of normal colorectal mucosa using monoclonal antibodies (MAbs). Staining results were related to histopathological features. HLA Class I antigens were strongly expressed in morphologically normal colorectal epithelium, in all adenomas tested and in all non-mucinous carcinomas. In contrast, expression of HLA class I antigens by the majority of tumour cells was present in only 2 of the 9 mucinous carcinomas, whereas 2 of these mucinous carcinomas were completely negative. In the mucinous carcinomas a striking scarcity of mononuclear inflammatory infiltrate, especially around the mucus accumulations, was observed. HLA class II antigen expression was not detected in normal epithelium and was only focally present in 1 of the 12 adenomas. In 6 out of the 20 carcinomas tested between 20% and 90% of the tumour cells were stained by MAbs against HLA class II antigens. Apart from the low expression of HLA class I antigens in mucinous carcinomas no relationship was found between expression of HLA antigens and histological features of the tumours. The relative poor prognosis of mucinous colorectal carcinoma as reported in the literature may be associated with low expression of HLA class I antigens and scant mononuclear inflammatory infiltrate, which may be a reflection of a weak immune response to the tumour cells.

The effects of indomethacin administration during pregnancy on women's and newborns' T-suppressor lymphocyte activity and on HLA class II expression by newborns' leukocytes.

It has been previously shown that T lymphocytes from human newborns and pregnant women exert a suppressive activity when assayed on the PWM-induced B cell maturation. The mechanisms of the suppression have remained entirely unknown. Prostaglandin E2, known to trigger T-cell mediated suppressive activity, may be involved. We took advantage of the treatment of pregnant women with indomethacin, because of premature labor or hydramnios, to investigate the role of prostaglandins in the activation of T suppressor (TS) activity. Administration of indomethacin (250 mg/day for 1-7 weeks, then 150 mg/day for 3-12 weeks) during the third trimester of pregnancy, abrogated the TS activity in the nine women and the three newborns tested. Abrogation of TS activity by indomethacin therapy led to normal PWM-induced B cell maturation in pregnant women but not in newborns. Moreover, the low expression of HLA class II antigens observed on normal newborn B lymphocytes and monocytes was corrected in newborns from indomethacin-treated mothers. Our results strongly suggest that prostaglandins may play a role in induction of TS activity observed in normal pregnant women and newborns and in the decreased expression of HLA class II antigens on newborns' leucocytes. Both phenomena could play a role in immunological interactions between mother and fetus.