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J Mouradian

Publications and source records attributed to J Mouradian.

At least 19 recordsLinked to original sources
PubMed2001

Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine.

BACKGROUND: Acute rejection is a serious and frequent complication of renal transplantation, and its diagnosis is contingent on the invasive procedure of allograft biopsy. A noninvasive diagnostic test for rejection could improve the outcome of transplantation. METHODS: We obtained 24 urine specimens from 22 renal-allograft recipients with a biopsy-confirmed episode of acute rejection and 127 samples from 63 recipients without evidence of acute rejection. RNA was isolated from the urinary cells. Messenger RNA (mRNA) encoding the cytotoxic proteins perforin and granzyme B and a constitutively expressed cyclophilin B gene were measured with the use of a competitive, quantitative polymerase chain reaction, and the level of expression was correlated with allograft status. RESULTS: The log-transformed mean (+/-SE) levels of perforin mRNA and granzyme B mRNA, which encode cytotoxic proteins, but not the levels of constitutively expressed cyclophiiin B mRNA, were higher in the urinary cells from the 22 patients with a biopsy-confirmed episode of acute rejection than in the 63 recipients without an episode of acute rejection (perforin, 1.4+/-0.3 vs. -0.6+/-0.2 fg per microgram of total RNA; P<0.001; and granzyme B, 1.2+/-0.3 vs. -0.9+/-0.2 fg per microgram of total RNA; P<0.001). Analysis involving the receiver-operating-characteristic curve demonstrated that acute rejection can be predicted with a sensitivity of 83 percent and a specificity of 83 percent with the use of a cutoff value of 0.9 fg of perforin mRNA per microgram of total RNA, and with a sensitivity of 79 percent and a specificity of 77 percent with the use of a cutoff value of 0.4 fg of granzyme B mRNA per microgram of total RNA. Sequential urine samples were obtained from 37 patients during the first nine days after transplantation; and measurements of the levels of mRNA that encoded cytotoxic proteins identified those in whom acute rejection developed. CONCLUSIONS: Measurement of mRNA encoding cytotoxic proteins in urinary cells offers a noninvasive means of diagnosing acute rejection of renal allografts.

Acute Disease↗
PubMed2000

Detection of chlamydial antigenic material in ovarian, prostatic, ectopic pregnancy and semen samples of culture-negative subjects.

PROBLEM: The pathogenesis of long-term sequelae in Chlamydia trachomatis infection is poorly understood. While serology indicates previous chlamydial infection, culture studies are frequently negative. We wanted to know whether in chronic cases the bacterium is absent or persists in a dormant state where it evades detection. METHODS OF STUDY: Using immunoperoxidase (IP) staining and in situ hybridization (ISH), we examined tissues of culture-negative subjects. Ovarian biopsy specimens from 19 culture-negative women with pelvic adhesions and/or tubal infertility were analyzed by both methods. Samples of prostates from 10 culture-negative men undergoing prostatectomy for benign hypertrophy, two sets of semen samples from culture-negative sexual partners of 28 women with PID and/or bacterial vaginosis (BV), and ten endometrium-tube sample-pairs from ectopic pregnancies (EPs) were examined by IP only. RESULTS: Seven of the nineteen ovarian specimens tested positive for Chlamydia antigen or deoxyribonucleic acid (DNA) (36%). Of the 10 hypertrophic prostates examined, 4 (40%) were positive. Of the 28 semen samples examined, 10 (35%) tested positive. Tissue samples of 3 cases of EP were positive by IP. CONCLUSIONS: 1. C. trachomatis antigen and nucleic acid can be frequently demonstrated in asymptomatic, culture-negative men and women with chronic infection. 2. Chlamydia antigens may have an etiologic role in benign prostate hypertrophy and EP. 3. Antigenic material may be sexually transmissible. 4. IP and ISH identify temporarily inactive bacteria that may continue to act as immunostimulants and potentially reactivate as Chlamydia infection.

Adult↗
PubMed1996

Molecular executors of cell death--differential intrarenal expression of Fas ligand, Fas, granzyme B, and perforin during acute and/or chronic rejection of human renal allografts.

Two distinct cytolytic pathways have been characterized: one in which the interaction between the Fas antigen and its ligand results in apoptosis, and another in which the pore forming protein perforin and the serine protease granzyme B contribute to DNA fragmentation and cell death. We investigated intrarenal expression of these molecular executors of cell death in light of the potential participation of cytolytically active cellular elements in the antiallograft repertory. Reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of Fas antigen, Fas ligand, granzyme B and perforin in eighty human renal allograft biopsies; mRNA display was correlated with the Banff histological diagnosis of renal allografts. Our studies demonstrate that: (1) intrarenal expression of Fas ligand mRNA and of granzyme B mRNA are correlates of acute but not chronic rejection; (2) Fas ligand mRNA is not detectable in allografts in the absence of rejection; (3) intrarenal coexpression of members of each lytic pathway (Fas ligand and Fas, granzyme B, and perforin) and that of both pathways (e.g., Fas ligand and granzyme B) are correlates of acute rejection; and (4) a direct correlation exists between the histological severity of acute rejection and intrarenal coexpression of mRNA encoding Fas ligand, Fas, granzyme B, and perforin. Our studies identify, for the first time, the differential expression of the two major lytic pathways in acute and chronic allograft rejection and suggest that specific therapy directed at the cytotoxic attack molecules might be efficacious in the prevention and/or treatment of acute rejection.

Acute Disease↗
PubMed1996

Intragraft TGF-beta 1 mRNA: a correlate of interstitial fibrosis and chronic allograft nephropathy.

Chronic allograft nephropathy is a relentlessly progressive process and a major cause of long-term graft dysfunction and ultimate failure. Interstitial fibrosis, tubular atrophy, and glomerular and vascular lesions characterize this mechanistically unresolved disorder. Given the prominent role of TGF-beta 1 in tissue repair and in fibrosis, we have explored the hypothesis that fibrosis and chronic allograft nephropathy would be distinguished by intragraft TGF-beta 1 mRNA expression. This postulate was tested by mRNA phenotyping of RNA isolated from 127 human renal allograft biopsies. Reverse transcription assisted polymerase chain reaction was used to amplify and identify ingraft gene expression. Our investigation demonstrated a significant correlation between intragraft TGF-beta 1 mRNA display and renal allograft interstitial fibrosis and chronic allograft nephropathy. In contrast, intragraft expression of mRNA encoding immunoregulatory cytokines, IL-2, IFN-gamma, IL-4, IL-10, or cytotoxic attack molecules, granzyme B and perforin was not a correlate of interstitial fibrosis or chronic allograft nephropathy. Our studies identify, for the first time, a significant association between intragraft TGF-beta 1 mRNA expression and renal allograft interstitial fibrosis, and advance a candidate molecular mechanism for chronic allograft nephropathy.

Base Sequence↗
PubMed1995

Intragraft expression of IL-10 messenger RNA: a novel correlate of renal allograft rejection.

A major conceptual advance is the formulation that type I cytokines (such as IL-2 and IFN-gamma) enhance cellular immunity and are host-protective, and that type II cytokines (such as IL-4 and IL-10) dampen cellular immunity and facilitate the progression of infection. We have explored the intragraft expression of type I and type II cytokines during human renal allograft rejection. RNA was isolated from 98 allograft biopsies, and reverse transcription-PCR was used to amplify and identify intragraft expression of mRNA encoding IL-2, IFN-gamma, IL-4, or IL-10. Intragraft expression of IL-7 mRNA and TGF-beta 1 mRNA was also investigated. Our investigation demonstrated that: (a) intragraft expression of IL-10 mRNA and IL-2 mRNA are significant correlates of acute rejection; (b) IL-4, IL-7, IFN-gamma and TGF-beta 1 mRNA expression do not correlate with acute rejection; and (c) IL-10 does not prevent in vivo expression of IFN-gamma, IL-2, IL-7, or TGF-beta 1. Our studies identify, for the first time, a significant association between intragraft IL-10 mRNA expression and acute rejection, and suggest that treatment strategies capable of constraining IL-10 expression might be of value in the prevention of acute rejection.

Base Sequence↗
PubMed1994

Immunotherapy with anti-CD3 monoclonal antibodies and recombinant interleukin 2: stimulation of molecular programs of cytotoxic killer cells and induction of tumor regression.

Adoptive cellular immunotherapy, infusions of interleukin 2 (IL-2) in conjunction with in vitro-activated killer cells, has brought new hope to patients with cancer. The broad application of this strategy, however, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in vitro activation of cells. Also, current protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells responsive to physiologic concentrations of IL-2 represents a potential improvement over existing approaches. We have determined whether in vivo administration of monoclonal antibodies (mAbs) directed at the T-cell surface protein CD3 induces T-cell responsiveness to IL-2, stimulates cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored in a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expression of mRNA-encoding perforin, cytotoxic T-cell-specific serine esterase, and tumor necrosis factor alpha. Anti-CD3 mAbs alone or IL-2 alone failed to induce or induced minimal expression of these molecular mediators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resulted in a significantly smaller number of hepatic metastases and a significantly longer survival time of tumor-bearing mice, compared to treatment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest that a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor regimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatment of cancer in humans.

Animals↗
PubMed1992

Analysis of autoantibody production in SCID-systemic lupus erythematosus (SLE) chimeras.

Mice with SCID disease have previously been successfully engrafted with human peripheral blood mononuclear cells (PBMC) obtained from normal individuals and from patients with various diseases. To determine whether SCID mice engrafted with SLE PBMC produced autoantibodies with specificities similar to those in the SLE donor, and to investigate which variables influence autoantibody production in the SCID recipients, we injected PBMC from 16 SLE patients into SCID mice and tested the recipients for autoantibodies to DNA and to five recombinant autoantigens. Ten out of 16 (68%) lupus and six out of nine (67%) normal grafts were successful as determined by the presence of human IgG greater than or equal to 5 micrograms/ml of SCID serum post-transfer. Autoantibodies to La/SSB, Ro/SSA, and RNP were detected in five out of 10 SCID-SLE recipients by ELISA and immunoblotting up to 22 weeks post-engraftment. The detection of autoantibodies in SCID-SLE mice was more closely related to autoantibody levels in donor sera than to total IgG concentrations in the SCID recipients. Autoantibody activity/mg IgG was similar in the donor and recipient sera. Histological evaluation of eight SCID-SLE mice killed 4-22 weeks post-transfer revealed population of the SCID thymus and spleen with mononuclear cells, but no evidence of lupus nephritis or dermatitis. These findings indicate that SCID mice can be engrafted with PBMC from patients with lupus and that specific autoantibodies are produced up to 5 months post-transfer. Failure to develop glomerulonephritis may be explained by low or absent anti-DNA antibodies or by changes in the cellular composition of the PBMC grafts.

Animals↗
PubMed1992

MRL/lpr-->severe combined immunodeficiency mouse allografts produce autoantibodies, acute graft-versus-host disease or a wasting syndrome depending on the source of cells.

MRL/lpr (lpr) mice spontaneously develop a lupus-like illness as well as massive lymphadenopathy. Attempts to transfer autoimmunity by adoptive transfer or radiation bone marrow chimeras have been unsuccessful. Since severe combined immunodeficiency (SCID) mice have been engrafted with human and rat xenografts without apparent graft-versus-host disease (GVHD), we subjected SCID mice to low-dose irradiation and reconstituted the mice with spleen cells from young or old lpr mice or with lpr bone marrow. Fourteen out of twenty (70%) of SCID mice engrafted with spleen cells from old lpr mice produced autoantibodies (anti-DNA and anti-Sm) without evidence of the severe lymphoid atrophy previously described for lpr spleen-->+/+ chimeras. SCID mice engrafted with spleen cells from young lpr mice developed acute GVHD and 5/6 (83%) died within 4 weeks post-transfer. Although 8/11 (73%) of lpr-->SCID bone marrow allografts survived for at least 4 months, these mice developed a wasting disease characterized by lymphoid atrophy and fibrosis without the production of autoantibodies. None of the lpr-->SCID grafts resulted in the transfer of double negative T cells or the lymphoproliferative syndrome characteristic of MRL/lpr mice. These findings indicate that SCID mice can be engrafted with splenocytes from old MRL/lpr mice and that B cells continue to secrete autoantibodies for several months in the SCID recipients. This study also demonstrates that, unlike i.p. transplant of xenogeneic cells, acute GVHD is a consistent feature of i.p. transplants of normal allogeneic mononuclear cells into SCID mice.

Animals↗
PubMed1990

Retroperitoneal accessory spleen.

We report a lower abdominal mass found to be a retroperitoneal accessory spleen. The vascular supply originated from retroperitoneal vessels independent of the splenic, testicular, and spermatic vessels.

Adult↗
PubMed1989

Progressive lymph node histology and its prognostic value in patients with acquired immunodeficiency syndrome and AIDS-related complex.

Seventy-four sequential lymph node biopsies from 30 acquired immunodeficiency syndrome (AIDS)/AIDS-related complex (ARC) patients showed temporal histologic progression from explosive follicular hyperplasia (EFH) to mixed follicular hyperplasia/involution (mixed) to follicular involution (FI) to lymphocyte depletion (LD). This histologic progression correlated with symptoms, development of opportunistic infections (OI), and mortality. At initial biopsy, only 50% of the AIDS/ARC patients with EFH/mixed compared to 100% with FI/LD were symptomatic with weight loss, night sweats, diarrhea, fever, or fatigue. 31% of ARC patients with EFH and 63% with FI developed an OI in a median of 69 months and 5 months, respectively; 86% with LD had a concurrent or previous OI. Ninety percent of ARC patients progressing to FI/LD died; 85% of those persisting with EFH/mixed remained alive 18 to 50 months after initial biopsy. AIDS patients with EFH lived twice as long as those with FI/LD. Progressive histology did not correlate with lymphoma. The number of ARC patients developing Kaposi's sarcoma was too small to draw definitive conclusions.

AIDS-Related Complex↗
PubMed1986

Immune complex glomerulopathy in a child with food hypersensitivity.

This report describes the occurrence of immune complex glomerulonephritis in a patient with eosinophilic gastroenteritis and food hypersensitivity. A coincident allergen injection may have been a contributing factor in the sudden development of the nephrotic syndrome. Markedly elevated levels of circulating immune complexes (greater than 6400 mg/dl) were found containing kappa-casein and bovine serum albumin (BSA), the latter predominating. Markedly elevated serum BSA hemagglutinating titers were also present (1:40,960). Cross-reacting precipitating antibodies to BSA, beef, and pork were demonstrated, but not to flounder or ovalbumin. Renal biopsy revealed immune complex glomerulonephritis with BSA, immunoglobulins M and G and complement deposited focally in the glomerular basement membrane. With strict dietary limitation of identified causative antigens and prednisone therapy, CIC levels decreased to 16,000 micrograms/dl and serum BSA antibody hemagglutinating titer fell 32-fold over a period of 15 months. There was prompt symptomatic relief and amelioration of signs of nephritis. The patient was able to consume a diet normal in protein and caloric content, and statural catch-up growth occurred. Recognition of food antigens to which the patient was hypersensitive provided a rationale for the relief of the gastrointestinal disturbance, growth stunting, and renal disease.

Adolescent↗
PubMed1985

Impact of renal donation. Long-term clinical and biochemical follow-up of living donors in a single center.

Forty-six renal donors who responded to a questionnaire and two additional donors with nephrotic syndrome and renal insufficiency were studied. The mean age was 46 +/- 2.0 years (mean +/- SE). Duration of follow-up was 6 +/- 0.5 years. Serum creatinine levels increased from 1.0 +/- 0.03 mg/dl before donation to 1.2 +/- 0.04 mg/dl at follow-up. The incidence of proteinuria (more than 150 mg over 24 hours) was 39 percent. The serum creatinine level was 1.0 +/- 0.08 mg/dl and 1.2 +/- 0.06 mg/dl in the proteinuric and nonproteinuric groups, respectively. The incidence of hypertension was 31 percent with a serum creatinine level of 1.1 +/- 0.11 mg/dl and 1.2 +/- 0.07 mg/dl in the hypertensive and normotensive groups, respectively. One patient with nephrotic syndrome had proliferative glomerulonephritis. It is concluded that renal donation is associated with a minimal but statistically significant increment in serum creatinine levels. The incidence of mild hypertension and proteinuria is increased, but impact on renal function is minimal as assessed by serum creatinine determination.

Adolescent↗
PubMed1984

Acquired immune deficiency syndrome. A surgical perspective.

Eighty-nine lymph node biopsies were performed on 82 patients with lymphadenopathy, immunosuppression, and possible acquired immune deficiency syndrome. The 21 patients with diagnoses of lymphoma or Kaposi's sarcoma were older, had more sexual contacts, and were sexually active for more years than patients with benign diagnoses. Cytomegalovirus and Epstein-Barr viral titers were elevated in both groups but were not significantly different in the benign and malignant groups. Skin flora were cultured from lymph node tissue in 24.7% of the patients. Two patients (2.5%) had wound infections with the same bacterium present in the lymph node culture, while 66 patients initially had two different benign pathologic patterns. Fifty-six patients had explosive follicular hyperplasia, and ten had follicular involution. Four of the patients with follicular involution and one with follicular hyperplasia subsequently had malignant tumors.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Mott cells in a patient with a lymphoproliferative disorder. Differentiation of a clone of B lymphocytes into Mott cells.

An unusual lymphoproliferative disorder characterized by diffuse infiltration of the bone marrow by lymphocytes and Mott cells without other organ involvement is described. The clinical course was remarkable for a spontaneous remission. The cells infiltrating the bone marrow were predominantly lymphocytes and Mott cells. The lymphocytes stained exclusively for membrane IgM-kappa by immunofluorescence, and the Mott cells contained typical Russell bodies staining in a rim pattern for IgM-kappa. These findings suggested that the lymphocytes were differentiating into Mott cells. This was demonstrated in vitro by stimulating peripheral blood lymphocytes with mitogens. Differentiation of B lymphocytes into Mott cells containing IgM-kappa was observed. These appeared to be identical to the Mott cells found in the marrow. The Mott cells were probably nonsecretory because of the absence of a monoclonal serum immunoglobulin. Electron microscopic studies showed that the electron-dense cytoplasmic inclusions resembled Russell bodies. This case probably represents an expanded clone of B lymphocytes with demonstrable in vivo and in vitro differentiation into Mott cells.

Aged↗