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J Forman

Publications and source records attributed to J Forman.

At least 37 records · Page 2Linked to original sources
PubMed1998

T cell vaccination induces T cell receptor Vbeta-specific Qa-1-restricted regulatory CD8(+) T cells.

Vaccination of mice with activated autoantigen-reactive CD4(+) T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8(+) regulatory T cells that are specific for pathogenic CD4(+) T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8(+) T cells emerge that preferentially lyse and regulate activated autologous CD4(+) T cells in a T cell receptor (TCR) Vbeta-specific manner. This TCR Vbeta-specific regulation is not observed in beta2-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vbeta8-specific Qa-1-restricted CD8(+) T cells are also induced by TCV with activated CD4(+) Vbeta8(+) T cells. These CD8(+) T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vbeta8. Further, CD8(+) T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4(+)Vbeta8(+) T cell clone specifically recognize other CD4(+) T cells and T cell tumors that express Vbeta8 and the syngeneic Qa-1(a) but not the allogeneic Qa-1(b) molecule. Thus, Vbeta-specific Qa-1-restricted CD8(+) T cells are induced by activated CD4(+) T cells. We suggest that these CD8(+) T cells may function to specifically regulate activated CD4(+) T cells during immune responses.

Animals↗
PubMed1998

Salvage surgery or salvage radiotherapy for locally recurrent prostate cancer.

OBJECTIVES: To evaluate the efficacy and toxicity of salvage radiation or surgery for locally recurrent tumor after initial treatment for clinically localized prostate cancer. METHODS: The treatment records of 70 patients with local treatment failure after definitive therapy for clinically localized prostate cancer were reviewed. Initial treatment consisted of external beam radiation therapy (RT) in 27 patients and radical retropubic prostatectomy (RP) in 43 patients. RESULTS: The mean serum PSA levels were similar in both groups before initial treatment: 8.5 and 10.5 ng/mL for the salvage RP and salvage RT groups, respectively (P = 0.09). However, at the time of salvage treatment, the mean serum PSA levels were 9.1 and 1.1 ng/mL for the salvage RP and salvage RT groups, respectively (P = 0.0001). The mean time from tumor recurrence to salvage treatment was 15.6 months for the salvage RP group and 4.9 months for the salvage RT group (P = 0.0001 ). Although there was no statistical difference in the disease-free survival rate (P = 0.38), a trend for better disease control in the salvage RT group was evident (74.4% versus 44.4%). Patients treated with salvage RP had a higher rate of urinary incontinence than those undergoing salvage RT: 63% and 32.6%, respectively (P = 0.01). CONCLUSIONS: The disease-free survival rate was similar between patients receiving salvage RP or RT, despite the significantly higher serum PSA levels at the time of treatment and the delay in time to treatment for the salvage RP patients. Salvage RP is associated with a high rate of urinary incontinence. Earlier identification of tumor recurrence after RT may improve the efficacy and safety of salvage RP.

Follow-Up Studies↗
PubMed1998

The pathway for processing leader-derived peptides that regulate the maturation and expression of Qa-1b.

Qa-1b and its human homolog, HLA-E, predominantly bind leader peptides derived from other class I molecules. Their presentation is TAP-dependent and proteasome-independent. We demonstrate that Dd targeted to the cytosol does not generate the Qa-1b peptide epitope even in the presence of lactacystin. Cells expressing herpes virus ICP-47 block the generation of this epitope, demonstrating that TAP functions in the transport of the peptide from cytosol to ER. This reveals a pathway for antigen presentation of leader peptides that involves translocation of a protein to the ER where its leader is cleaved followed by its release into the cytosol and transport back into the ER. Further, it ensures that Qa-1b expression mirrors the normal expression of class Ia molecules.

Acetylcysteine↗
PubMed1998

Listeria monocytogenes-infected hepatocytes are targets of major histocompatibility complex class Ib-restricted antilisterial cytotoxic T lymphocytes.

Subclinical infection of BALB/c mice with the intracellular bacterial pathogen Listeria monocytogenes results in the development of protective antilisterial immunity. L. monocytogenes can infect hepatocytes, and antilisterial cytotoxic T lymphocytes (CTL) lyse Listeria-infected hepatocytes in a major histocompatibility complex (MHC) class Ia-restricted manner. It remained to be determined whether L. monocytogenes-infected hepatocytes are susceptible to MHC class Ib-restricted cytolysis. In this study, we showed that hepatocytes express MHC class Ib molecule Qa-1(b) mRNA and protein. We further showed that Listeria-infected hepatocytes are susceptible to MHC class Ib-restricted cytolysis, since C57BL/6-derived Listeria-infected hepatocytes were lysed by BALB/c-derived antilisterial CTL. These results establish that Listeria-infected hepatocytes are susceptible to cytolysis by MHC class Ib restricted Listeria-specific CTL.

Animals↗
PubMed1998

Vaccination with a recombinant vesicular stomatitis virus expressing an influenza virus hemagglutinin provides complete protection from influenza virus challenge.

Since the development of a system for generating vesicular stomatitis virus (VSV) from plasmid DNAs, our laboratory has reported the expression of several different glycoproteins from recombinant VSVs. In one of these studies, high-level expression of an influenza virus hemagglutinin (HA) from a recombinant VSV-HA and efficient incorporation of the HA protein into the virions was reported (E. Kretzschmar, L. Buonocore, M. J. Schnell, and J. K. Rose, J. Virol. 71:5982-5989, 1997). We report here that VSV-HA is an effective intranasal vaccine vector that raises high levels of neutralizing antibody to influenza virus and completely protects mice from bronchial pneumonia caused by challenge with a lethal dose of influenza A virus. Additionally, these recombinant VSVs are less pathogenic than wild-type VSV (serotype Indiana). This vector-associated pathogenicity was subsequently eliminated through introduction of specific attenuating deletions. These live attenuated recombinant VSVs have great potential as vaccine vectors.

Administration, Inhalation↗
PubMed1998

Phase II trial of sequential radiation and interleukin 2 in the treatment of patients with metastatic renal cell carcinoma.

We have previously demonstrated that local tumor irradiation effectively enhanced the therapeutic effect of interleukin 2 (IL-2) therapy in an experimental murine renal adenocarcinoma model. Based on these preclinical studies, we have designed and initiated a Phase II trial of irradiation combined with IL-2 for the treatment of metastatic renal cell carcinoma. Patients received 800 cGy to the primary or metastatic lesions on days 1 and 15 followed by IL-2 (600,000 IU/kg i.v.) every 8 h on days 4-8 and 18-22. Sixteen patients were entered; all completed treatment and are therefore evaluable for toxicity and response. Two partial remissions were seen for a response rate of 12.5% (95% confidence interval, 0-28.7). There was no increase in toxicity over that which is anticipated from IL-2 alone. The antitumor activity seen in this trial is consistent with what would be expected from high-dose IL-2 alone.

Adult↗
PubMed1998

Expression of bcl-2, p53, and p21 in benign and malignant prostatic tissue before and after radiation therapy.

Abnormalities in genes of the apoptotic pathway might contribute to survival in prostatic cancer (PCa) cells after radiation therapy (RT). We investigated the immunohistochemical expression of the products of the p53, p21WAF1, and bcl-2 genes in pre-RT and post-RT biopsy specimens from 38 patients with locally advanced PCa. All of the 38 patients underwent a uniform protocol of RT with or without neoadjuvant hormonal therapy. Immunohistochemical staining for expression of the products of the p53, p21WAF1, and bcl-2 genes was performed on material from pre-RT and post-RT specimens. Sufficient tissue for analysis was available from 25 of the pre-RT and 38 of the post-RT biopsy specimens. In benign prostatic epithelium, RT resulted in expression of p53 (2 [8%] of 25 pre-RT specimens vs. 15 [71%] of 21 post-RT specimens; P < .001) and increased expression of bcl-2 (1 [5%] of 18 pre-RT vs. 18 [86%] of 21 post-RT; P < .001). There was no change in the expression of p21WAF1 (1 [4.5%] of 22 pre-RT vs. 4 [17%] of 23 post-RT; P = NS). Post-RT specimens were positive for PCa in 24 (63%) of 38 cases. In the PCa tissue, p53 expression was seen in 10 (42%) of 24 pre-RT and 12 (63%) of 19 post-RT samples (P = NS). A significant upregulation of p53 was seen in the subgroup of patients who did not receive neoadjuvant hormonal therapy (9 [82%] of 11 vs. 3 [38%] of 8; P = .05). No significant change in p21WAF1 (5 [21%] of 24 vs. 5 [33%] of 15; P = NS), or bcl-2 (4 [18%] of 22 vs. 3 [21%] of 14; P = NS) expression was detected. There was no significant correlation between immunohistochemical expression of apoptosis-related markers and treatment failure. We concluded that RT induced upregulation of the bcl-2 and p53 gene products in benign prostatic tissue and that this likely reflected a protective mechanism in genetically unaltered epithelium. Increased p53 expression in PCa was only seen in patients without neoadjuvant hormonal treatment, indicating that the cancer cells with abnormal p53 were at least partially protected from RT-induced cell death.

Adult↗
PubMed1997

MHC class Ib-restricted cells contribute to antilisterial immunity: evidence for Qa-1b as a key restricting element for Listeria-specific CTLs.

Subclinical infection of BALB/c mice with the intracellular pathogen Listeria monocytogenes results in the development of MHC class Ia- and Ib-restricted CTLs. L. monocytogenes-infected TAP-/- bone marrow macrophage targets are not lysed by MHC class Ia- or Ib-restricted CTLs, showing a requirement for transport of peptides into the endoplasmic reticulum for development of the MHC class Ib-peptide target. L. monocytogenes-infected B6.Tla(a)-derived bone marrow macrophages (Kb Qa-1a) are not lysed by BALB/c (Kd Qa-1b)-derived antilisterial CTLs, confirming an earlier finding that the Ib-restricting element is T region encoded. We have further determined that Qa-1b is a restricting element for antilisterial CTLs using L. monocytogenes-infected Qa-1b-transformed mouse L cells as well as human-derived HeLa cells as target populations. These L. monocytogenes-infected Qa-1b-transformed cell lines are lysed by BALB/c (Qa-1b)- or C57BL/6 (Qa-1b)-derived antilisterial CTLs, but are not lysed by B6.AKM (Qa-1a)-derived antilisterial CTLs. Using L. monocytogenes-infected targets, we found that MHC class Ia- and Ib-restricted CTLs are evident within 4 days following infection, peak on day 5 following infection, and although Ib-restricted CTLs disappear by day 6 postinfection, la-restricted antilisterial CTL activity can still be detected. These results demonstrate that Qa-1b is a restricting element for antilisterial CTLs, and expression of the MHC class Ib-presented target at the cell surface is TAP dependent. In addition, these results show that following L. monocytogenes infection, MHC class Ib-restricted CTLs are evident in vivo.

Animals↗
PubMed1997

The effect of the proteasome inhibitor lactacystin on the presentation of transporter associated with antigen processing (TAP)-dependent and TAP-independent peptide epitopes by class I molecules.

Cells were treated with two proteolytic inhibitors, N-acetyl-leucyl-leucyl-norleucinal and lactacystin, the latter reported to be a specific inhibitor for the proteasome. Both inhibitors retarded the maturation of endo-H-resistant forms of murine and human class I molecules from their endo-H-sensitive precursors in cell lines with functional TAP proteins. HLA-A2 maturation readily occurs in TAP-deficient T2 cells, and it has been shown that the peptides associated with A2 are derived from the leader segment of proteins in the secretory pathway. This maturation is inhibited by N-acetyl-leucyl-leucyl-norleucinal but not lactacystin, indicating that the proteasome is not required for the generation of HLA-A2 binding peptides in these cells. The murine class Ib molecule Qa-1b presents a leader peptide derived from D-end class I molecules to alloreactive CTL. Since this presentation is dependent on the expression of TAP proteins, we determined if this requirement reflects a need for the proteasome to process this peptide. We found that lactacystin did not inhibit the maturation of endo-H-resistant forms of Qa-1b that are dependent on this leader peptide for its maturation, nor did it inhibit the expression of this peptide-Qa-1b complex in a functional assay. Thus, unlike conventional cytosolic peptides, leader peptides (regardless of whether they are dependent on TAP for their presentation) do not require the proteasome for processing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Peptide binding to the class Ib molecule, Qa-1b.

We have analyzed the interaction of a nonameric peptide (Qdm) derived from the leader sequence of a MHC D region molecule with the class Ib molecule, Qa-1b. Using a direct binding assay with radiolabeled peptide on intact cells, we show specific binding of iodinated Qdm peptide to Qa-1b expressing cells. Specificity was confirmed by experiments in which the binding of iodinated peptide was blocked by unlabeled Qdm and not by control peptides. This allowed us to determine the on- and off-rate of peptide binding to Qa-1b, its binding affinity, and number of available peptide-binding sites per cell. Optimal binding occurs at 4 degrees C, and most of the binding to Qa-1b occurs within the first 10 min and peaks after 3 h. The dissociation of the peptide from cells has a t1/2 of approximately 10 h. The Kd is calculated between 0.2 and 1.1 x 10(-10) M, which is in the range or slightly higher than the Kd we measured for pMCMV to Ld (0.9 x 10(-10) M). The relatively high affinity of binding of the Qdm peptide and low dissociation rate could partially explain why a large portion of Qa-1b molecules are occupied with this single peptide species. We also changed each peptide residue to Ala or Gly to determine its effect on binding. Substitution of Leu at position 9 to Ala strongly reduced peptide binding, while changes at positions 2 (Met-->Ala) and 5 (Arg-->Ala) had a lesser effect. Binding to Qa-1b was completely abrogated with simultaneous Ala mutations at positions 2 and 9.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Dominance of a single peptide bound to the class I(B) molecule, Qa-1b.

One of the hallmarks of class I(A) molecules is their ability to bind and present a wide array of peptides to CD8 T cells. This diversity is consistent with their ability to restrict a variety of pathogenic peptide epitopes as well as elicit strong transplantation responses. In contrast, class I(B) molecules appear to be involved in presentation of pathogenic epitopes to a relatively lesser extent as well as play a minor role in transplantation responses. Here we have examined the peptides bound and presented by the class I(B) molecule Qa-1b in order to determine if their diversity was similar to that reported for class I(A) Ags. First, we show that bulk-cultured anti-Qa-1b CTL predominantly recognize a single peptide (Qdm) derived from the leader segment of class I(A) alloantigens. These CTL are peptide specific and reflect the activity of previously described CTL clones. Second, we find approximately 4.6 x 10(4) copies of the Qdm peptide/cell. Most of the peptide is Qa-1b associated since the recovery of this peptide from anti-Qa-1b immunoprecipitates is approximately 75% of that seen in whole cell extracts and no detectable activity is observed in Kb or Db extracts from H-2b lymphoblasts. Third, the expression of Qa-1b on lymphoblasts is approximately 1 to 1.25 x 10(4) molecules/cell indicating that the Qdm peptide must be derived from both cell membrane and intracellular compartments. Finally, examination of the diversity of peptides associated with Qa-1b as determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry indicates few detectable peptide species associated with this molecule. Taken together, Qa-1b appears to predominantly bind a single peptide species that is recognized by alloreactive CD8 T cells. This feature may account, in part, for the class I(B) properties of this molecule.

Animals↗
PubMed1997

Myocardial infarction resulting from caffeine overdose in an anorectic woman.

A 20-year-old bulimic woman ingested 20 g of caffeine in a suicide attempt. After being evaluated and discharged from the emergency department, she was readmitted with ECG changes and ultimately found to have sustained a subendocardial infarction. This case highlights the wide-ranging health consequences of eating disorders and the toxicity of caffeine overdose.

Adult↗
PubMed1997

Interaction of 2C T cells with a hybrid Ld molecule bearing an alpha 3 domain derived from the class IB molecule, Qa-2.

The CD8 co-receptor interacts with nonpolymorphic residues on class I molecules. LQ3, a laboratory engineered Ld molecule bearing an alpha 3 domain derived from Q7 (Qa-2), interacts poorly with anti-Ld CD8-dependent T cells. 2C TCR transgenic mice bear a receptor specific for the p2Ca peptide bound to Ld. The authors show that although this peptide interacts with LQ3, LQ3 APC fail to activate splenic 2C CD8 T cells in vitro in the absence of IL-2, while control Ld APC do. The authors have used this receptor ligand pair to examine negative selection within the thymus of (B6 x C3H.Ld)F1 versus (B6 x C3H.LQ3)F1 radiation chimeras repopulated with 2C bone marrow cells. While positive selection occurs normally in (B6 x C3H)F1 chimeras, animals expressing either Ld or LQ3 fail to generate 2C CD8+ cells. Thus, either CD8 is not required for negative selection of this TCR or a weak interaction of CD8 with LQ3 is sufficient. TSA-1, a developmentally regulated marker, was used to follow the process of negative selection. The results show that deletion of 2C T cells does not occur until thymocytes reach the double positive (DP) stage. Furthermore, the authors noted a small population of DP TSA-1hi cells remains, while DP TSA-1int and TSA-1lo cells are absent. These data support the notion that thymocytes either reach a particular stage of development or locate in an appropriate intrathymic compartment before they undergo negative selection.

Animals↗
PubMed1995

Three dimensional conformal radiotherapy for the treatment of prostate cancer: low risk of chronic rectal morbidity observed in a large series of patients.

PURPOSE: Three dimensional conformal radiotherapy (3D CRT) may provide a technique to increase the dose delivered to target tissues while sparing uninvolved normal structures. To evaluate the role of 3D treatment in reducing the treatment toxicity, we analyzed the chronic rectal morbidity observed in a large group of patients undergoing radiotherapy for prostate cancer. METHODS AND MATERIALS: From 1987 through 1992, 721 prostate cancer patients were treated with 3D CRT at the University of Michigan or Providence Hospital. All had axial computed tomography (CT) specifically for RT planning, multiple structures contoured on the axial images, and beam's-eye-view conformal beams edited to provide 3D dose coverage. Using current American Joint Commission (AJCC) staging, 537 patients had T1-T2 tumors, 123 had T3-T4 tumors, and 60 were treated postprostatectomy. Pelvic lymph nodes were treated in 462 patients. Prostate boosts were delivered with four-field axial, six-field axial, or four-field oblique, nonaxial fields. The median dose was 68.40 Gy (range 59.4-80.4). Median follow-up was 20.4 months; 175 were followed more than 3 years. All complications have been graded conservatively using the RTOG system. RESULTS: Using a Cox proportional hazard's model, patient age, T-stage, prescribed dose, pelvic treatment, and boost technique were analyzed. The factor most strongly related to risk of morbidity was dose (p = 0.05); however, the boost technique was also related: the four-field oblique field had the lowest relative risk. Most episodes of rectal morbidity have been mild: 82 Grade 1 or 2. There have been only 14 more serious complications including 12 Grade 3 and 2 Grade 4. The actuarial risk of a Grade 3 or 4 complication is 3% at 3 and 5 years. CONCLUSIONS: A very small proportion of patients treated with 3D CRT had significant rectal morbidity related to RT, supporting the use of conformal treatment planning and dose delivery as a mechanism to minimize complications in the treatment of prostate cancer.

Adenocarcinoma↗
PubMed1995

Dose-related effect of IGF-I on placental prostanoid release.

Prostanoids play an important role throughout all of pregnancy and during the initiation and progress of labor. The human placenta at term produces large quantities of prostanoids, yet little is known of the factors regulating their biosynthesis. In a previous study we observed that insulin-like growth factor I (IGF-I) specifically inhibits thromboxane B2 (TxB2) and prostaglandin F2 alpha (PGF2 alpha) from human term placental explants. In these studies we have defined the dose-related action of IGF-I on the release of placental prostanoids. With use of a perifusion system, the basal release of prostaglandin E2 (PGE2), PGF2 alpha, TxB2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) from human term placental explants increased from the fifth hour in culture, while the release of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) remained constant. The addition of IGF-I (5.2-83.3 ng/mL) to the perifusing medium effected an inhibition of TxB2 and PGF2 alpha. The release of TxB2 was inhibited in a dose-related fashion from the initiation of IGF-I treatment and throughout the five hours of treatment, whereas the inhibition of PGF2 alpha was significant only at a dose of 83.3 ng/mL of IGF-I. Yet, the release of 6-keto-PGF1 alpha, PGE2, or PGFM was not altered by any dose of IGF-I studied. Because both TxB2 and PGF2 alpha are vasoconstrictors, we have proposed that IGF-I may enhance vasodilation in the placenta. Therefore, IGF-I may allow for increased blood flow, thus affecting the maintenance of pregnancy and the supply of nutrients available for the growth of the fetus.

Dinoprost↗
PubMed1995

Novel molecules related to MHC antigens.

Several types of molecules related to classical class I and II antigens of the MHC have been recently discovered. At the same time we have learnt more about the functions of non-classical (class Ib) antigens. This has shed light on the possible evolutionary origins and the likely roles that these molecules may play in the immune response.

Animals↗