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Biomedical subjects

M Colonna

Publications and source records attributed to M Colonna.

At least 109 records · Page 6Linked to original sources
PubMed1997

Human histocompatibility leukocyte antigen (HLA)-G molecules inhibit NKAT3 expressing natural killer cells.

The crucial immunological function of the classical human major histocompatibility complex (MHC) class I molecules, human histocompatibility leukocyte antigen (HLA)-A, -B, and -C, is the presentation of peptides to T cells. A secondary function is the inhibition of natural killer (NK) cells, mediated by binding of class I molecules to NK receptors. In contrast, the function of the nonclassical human MHC class I molecules, HLA-E, -F, and -G, is still a mystery. The specific expression of HLA-G in placental trophoblast suggests an important role for this molecule in the immunological interaction between mother and child. The fetus, semiallograft by its genotype, escapes maternal allorecognition by downregulation of HLA-A and HLA-B molecules at this interface. It has been suggested that the maternal NK recognition of this downregulation is balanced by the expression of HLA-G, thus preventing damage to the placenta. Here, we describe the partial inhibition of NK lysis of the MHC class I negative cell line LCL721.221 upon HLA-G transfection. We present three NK lines that are inhibited via the interaction of their NKAT3 receptor with HLA-G and with HLA-Bw4 molecules. Inhibition can be blocked by the anti-NKAT3 antibody 5.133. In conclusion, NK inhibition by HLA-G via NKAT3 may contribute to the survival of the fetal semiallograft in the mother during pregnancy.

Cells, Cultured↗
PubMed1997

Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways.

We have identified two novel human cDNA encoding transmembrane proteins of the immunoglobulin superfamily (IgSF). The two cDNA, called immunoglobulin-like transcripts 1 and 2 (ILT1 and ILT2), are expressed in myeloid and lymphoid cells and are homologous to bovine Fc gamma2R, human killer cell inhibitory receptors (KIR), human Fc alphaR, and mouse gp49. Furthermore, ILT1 and ILT2 are encoded on chromosome 19, as are Fc alphaR and KIR. While the ILT1 and ILT2 extracellular domains are homologous, the transmembrane and cytoplasmic domains differ substantially. ILT1 has an arginine within the transmembrane region, followed by a short cytoplasmic tail, similar to human Fc alphaRI and bovine Fc gamma2R. ILT2 has a long cytoplasmic tail, which contains two YxxV and two YxxL pairs similar to the immunoreceptor tyrosine-based inhibitory motifs in KIR that are known to bind the phosphotyrosine phosphatase SHP-1. These cytoplasmic features suggest that ILT1 and ILT2 may mediate novel transmembrane signals by which myeloid and lymphoid cell responses can be either activated or inhibited.

Alternative Splicing↗
PubMed1997

HLA-A typing: comparison between serology, the amplification refractory mutation system with polymerase chain reaction and sequencing.

In this study we typed HLA-A polymorphisms by a new sequence-based typing (SBT) method, which involved one PCR reaction and four sequencing reactions covering exon 2 and exon 3. This method allowed complete identification of all known HLA-A alleles and revealed the presence of a new allele, named HLA-A*2608. We also introduced sequencing of exon 4 for some samples in order to discriminate the allelic pairs that are identical in exon 2 and 3, thus improving SBT resolution. Finally, we compared the results obtained by SBT with data obtained by serological typing and the amplification refractory mutation system (ARMS-PCR). Together, our results suggest that the SBT here described provides an optimal HLA-A typing technique that may be useful in selecting donor-recipient pairs in bone marrow transplantation between unrelated individuals.

Adult↗
PubMed1997

Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors.

Human NK cells express clonally distributed receptors specific for HLA-A, -B and -C molecules. These receptors belong to the immunoglobulin superfamily and can be functionally distinguished as inhibitory or stimulatory. Inhibitory receptors block NK-cell-mediated cytotoxicity upon binding to HLA class I ligands. This function is mediated by phosphorylation of cytoplasmic tyrosines, which recruit the protein tyrosine phosphatase SHP-1. Stimulatory receptors also bind HLA class I, lack cytoplasmic tyrosine-based motifs, and trigger NK cytotoxicity and proliferation. Both types of receptor are characterized by a limited diversity allowing for recognition of distinct class I supertypic epitopes. This limited diversity is counterbalanced by the expression of different combinations of inhibitory and stimulatory receptors with self and/or non-self HLA class I specificities on distinct NK cell clones. This peculiar strategy allows NK cells to detect loss of MHC class I molecules on autologous transformed and virally infected cells with maximal sensitivity.

Antibody Specificity↗
PubMed1997

Major histocompatibility complex (MHC) class I recognition by natural killer cells.

NK cells express clonally distributed receptors specific for MHC class I molecules. Structurally, these receptors belong to the C-type lectin superfamily in mouse and to the immunoglobulin superfamily in human. Functionally, they can be distinguished as inhibitory or stimulatory. Inhibitory receptors block NK cell-mediated cytotoxicity upon binding to HLA class I ligands. This function is mediated by phosphorylation of cytoplasmic tyrosines, which recruit the protein tyrosine phosphatase SHP-1. Stimulatory receptors also bind HLA class I, lack cytoplasmic tyrosine-based motifs, and trigger NK cell-mediated cytotoxicity. All these receptors are characterized by a limited diversity allowing for sensitive detection of loss of MHC class I molecules on autologous transformed and virally infected cells.

Animals↗
PubMed1997

[Evaluation of survival and prognostic factors of 2,000 broncho-pulmonary cancers registered during 10 years in a multidisciplinary oncology department].

Two thousand lung cancer patients were registered as Grenoble's university hospital joint oncology clinic from 1/1/1982 to 12/31/1991. These cases consisted of 449 small cell lung cancers (SCLC) and 1,551 non-small cell lung cancers (NSCLC). SCLC patients had a 4.6% and 2.9% survival rate at 5 and 10 years and only 7.2% of patients had a survival longer than 30 months. The main prognostic factors for survival were age, sex, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study. NSCLC patients had a 14% and 7% survival rate at 5 and 10 years. Among 727 stage III or IV patients not treated with surgery, 2% were alive at 30 months. The main prognostic factors for survival were age, histology, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study.

Adult↗
PubMed1997

[Prevalence assessment of colorectal and breast cancers in the Rhône-Alpes area].

Prevalence of malignant neoplasm is a basic health indicator used in order to evaluate needs in medical equipment for treatment and follow-up of cancer patients. Data on prevalence are regularly published by Northern European countries. Thames and Connecticut cancer registries. In France available information on prevalence are scanty, because follow-up of cancer patients is not easy. Therefore, we used a statistical method to evaluate prevalence from incidence and mortality in the Rhône-Alpes area (France, 5,300,000 inhabitants) in 1990, using the department of Isère population based registry. For females, figures for breast carcinoma and colorectal carcinoma are respectively 25,000 and 5,700, and, for males, 5,700 colorectal carcinoma. For 5 year partial prevalence, these figures are respectively 11,300, 3,100 and 3,500. The ratio prevalence/incidence is 8.9 for breast in females, 5.8 for colorectal carcinoma in females and 4.8 for colorectal carcinoma in males with a steep decrease for 5 year partial prevalence (4 for breast carcinoma, 3.1 for females colorectal carcinoma and 2.9 for males colorectal carcinoma). These ratios are consistent with those observed elsewhere in Europe.

Adult↗
PubMed1997

[Empirical Bayes estimates of relative risk: principles and examples].

Most atlases, such as cancer incidence or mortality atlases, show information for geographical subunits with major differences in population size. Under such conditions, classical epidemiological mapping indexes (SIR, SMR) are unsatisfactory. Regional pattern, if they exist, cannot be shown. Empirical Bayes methods produce smoothed relative risk estimators useful for solving this problem. We present some elementary principles of these methods using cancer incidence data in the French department of Isere.

Bayes Theorem↗
PubMed1997

[Combination of induction chemotherapy with surgery and/or radiotherapy in locally advanced head and neck cancers. A retrospective analysis of a series of 125 patients].

The prognosis of locally advanced cancers of the head and the neck is pejorative, particularly when nodal involvement is present. In order to improve local control and to reduce distant failures, we have treated stages III and IV patients with induction chemotherapy. From May 1986 to November 1992, 125 patients with squamous cell carcinoma of the head and neck were treated by induction chemotherapy: cisplatine (100 mg/m2 at J1) and 5FU (1 g/m2 from J1 to J5 in continuous infusion) every 21 days subsequent local therapy consisted of surgery for patients with resectable disease, and/or radiotherapy. One hundred and nineteen patients were assessable (110 men and 9 women) with a median age of 57 years (range: 36-78). All patients had performance status inferior or equal to 2. According to the TNM of UICC classification 50 patients were stage IV (42%), 61 stage III (51%), 7 stage II (6%) and a stage I (1%). One hundred (84%) patients have received at least 3 cycles of chemotherapy. Seventy-four patients (62%, IC: 60.4-63.5) had clinical objective response (complete response (CR) or partial response (PR)) with 24 patients (20%) CR and 50 patients (42%) PR. Local therapy included surgery in 81 patients (68%) and radiotherapy alone in 42 patients (35%). Overall, 103 patients (87%) were rendered clinically disease-free by treatment on this protocol. The toxicities of cisplatine and 5-FU chemotherapy consisted predominantly of myelosuppression (5%) and renal toxicities (4%) and were moderate as described for this combination. At a median follow-up of 32 months, the median survival is 38 months (CI 95%, 18-54 months), and the median time to progression is 62 months. The oropharynx localization reached statistical significance for survival rates (Log-rank test, p = 0.02).

Adult↗
PubMed1996

Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules.

Recognition of major histocompatibility complex class I molecules by natural killer (NR) cells leads to inhibition of target cell lysis. Based on the capacity of different human histocompatibility leukocyte antigen (HLA)-C and HLA-B molecules to inhibit target cell lysis by NK lines and clones, three NK allospecificities have been defined: NK1 and NK2 cells are inhibited by different HLA-C allotypes and NK3 cells by some HLA-B allotypes. The NK1 and NK2 inhibitory ligands on target cells correspond to a dimorphism of HLA-C at residues 77 and 80 in the alpha 1 helix: Asn77-Lys80 in NK1 and Ser77-Asn80 in NK2 inhibitory ligands. It has been reported that protection from NK1 killers depended on the presence of the Lys residue at position 80, an upward pointing residue near the end of the alpha 1 helix (and not on Asn77), whereas inhibition of NK2 effector cells required Ser77, a residue deep in the F pocket and interacting with the peptide (and not Asn80). As part of ongoing experiments to investigate the structural requirements for NK cell inhibition by HLA-C locus alleles, we also examined the effects of mutations at residues 77 and 80 on the ability of HLA-C alleles to confer protection from NK lysis. We present data confirming that the NK1 specificity depended on Lys80 (and not on Asn77); however recognition of NK2 ligands by NK cells was also controlled by the amino acid at position 80 (Asn), and mutation of Ser77 had no effect. Furthermore, bound peptide was shown to be unnecessary for the inhibition of NK cell-mediated lysis since HLA-C molecules assembled in the absence of peptide in RMA-S cells at 26 degrees C were fully competent to inhibit NK cells specifically. The implications of these data for peptide-independent recognition of HLA-C by NK receptors are discussed.

Alleles↗
PubMed1996

Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C.

Natural killer (NK) cells express killer inhibitory receptors that mediate negative regulation of NK cell cytotoxicity upon binding to MHC class I molecules on target cells. Unrelated inhibitory receptors on B cells have recently been shown to function through recruitment of phosphotyrosine phosphatase 1C (PTP-1C). Here, we show that a human killer inhibitory receptor specific for HLA-C also recruits PTP-1C after phosphorylation induced either by the pharmacological agent phenylarsine oxide or by conjugation with target cells. This recruitment is mediated by the binding of specific cytoplasmic phosphotyrosine-containing sequences to PTP-1C. These results implicate PTP-1C as a cytosolic component of the negative signaling pathway through NK cell inhibitory receptors.

Amino Acid Sequence↗
PubMed1996

A human killer inhibitory receptor specific for HLA-A1,2.

Killer inhibitory receptors (KIRs) are transmembrane glycoproteins, expressed on NK cells and a small subset of T cells, that inhibit cell-mediated cytotoxicity upon binding to polymorphic MHC class I determinants on target cells. Although human KIRs specific for HLA-C and HLA-B molecules have been characterized, none have been shown to interact with HLA-A. Here we demonstrate that a member of the KIR cDNA family, designated NKAT4, encodes a 70-kDa receptor specific for HLA-A3.

Antibodies, Monoclonal↗
PubMed1996

Human natural killer cell inhibitory receptors bind to HLA class I molecules.

To obtain direct evidence that human natural killer cell (NK) inhibitory receptors physically interact with polymorphic determinants of major histocompatibility complex class I molecules, a receptor termed NK-associated transcript-2 has been produced as a soluble fusion protein with the human IgG1 Fc portion. This soluble receptor binds specifically to HLA-C alleles with serine 77 and asparagine 80 in cell adhesion assays.

Alleles↗
PubMed1996

Natural killer clones recognize specific soluble HLA class I molecules.

Enhancement of major histocompatibility complex (MHC) class I expression leads to protection from natural killer (NK) cell recognition in several systems. MHC class I gene products are released from the cell surface and can be found in sera as soluble forms. To investigate the possible immunoregulatory role of soluble HLA (sHLA) in NK cell-target recognition, several sHLA antigens were studied for their ability to induce NK cell cytotoxicity modulation. NK cell-target recognition was inhibited by the addition of sHLA during the cytotoxicity assay. Our results indicate that sHLA molecules can down-regulate NK killing at the effector level. Moreover, different NK clones are able to specifically recognize different sHLA antigens. Kp43 molecules seem to be involved in the NK recognition of sHLA-B7.

Antigens, CD↗
PubMed1996

Severe head injuries: an outcome prediction and survival analysis.

OBJECTIVE: To identify the predictors determined early after admission and associated with unfavorable outcome or early (within 48 h) death after severe head injury. DESIGN: Prospective cohort study. SETTING: A neurosurgical intensive care unit in a university hospital. PATIENTS: 198 consecutive comatose patients hospitalized from 1989 to 1992. RESULTS: Logistic regression showed that a combination of age, best motor response score from the Glasgow Coma Scale, and hypoxia provided a good prediction model of unfavorable outcome (sensitivity = 0.93). The length of participation of survivors was 6 to 61 months (median 27.1). The Cox model demonstrated age, motor score less than 3, mydriasis, and hypoxia as poor prognosis factors. CONCLUSIONS: Clinicians can determine the odds of a good outcome from the combination of three easily measurable factors using a simple diagram constructed from logistic regression. Survival analysis showed that motor score adjusted values greater than 3 had the same prognosis.

Adult↗
PubMed1996

Protein tyrosine kinase activity in 350 T1/T2, N0/N1 breast cancer. Preliminary results.

Protein tyrosine kinases (PTKs) are a family of enzymes sharing a highly conserved catalytic domain which phosphorylates substrate proteins on tyrosine residues. PTKs play a major role in the transduction of the mitogenic signal and are involved in the control of cell proliferation, differentiation, and transformation processes. PTKs can be subdivided into two major types: membrane associated PTKs consisting essentially of growth factor receptors (receptor tyrosine kinases or RTKs) and cytosolic PTKs involved in the intracellular transduction of mitogenic and differentiation signals. From January 1988 to January 1992, PTK activity was assayed in cytosolic fractions prepared from 350 T1-T2, N0-N1 M0, breast carcinomas. Enzymatic activity was measured using phosphate transfer from [32P]-ATP to poly-Glu-Tyr as an artificial substrate. According to our previously reported pilot study, we chose a cut-off value of 12 pmol 32P incorporated min-1 mg-1 protein, corresponding to the median value. We found positive PTK levels (> or = 12 pmol/min/mg) to be correlated with a loss of differentiation according to Scarff-Bloom grade (p < 0.001), negative PR (p = 0.03) and ER status (p = 0.04). With a median follow-up of 30 months (0-82), patients with a positive PTK level presented a smaller 3-year disease free survival than in the PTK negative group of patients (p = 0.07). In Cox multivariate analysis including pT, pN, Scarff-Bloom grade, PR and ER, PTK activity does not emerge as a significant prognostic factor.

Adult↗