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Biomedical subjects

M J Dallman

Publications and source records attributed to M J Dallman.

At least 55 records · Page 3Linked to original sources
PubMed1993

Specific tolerance to neural allografts induced with an antibody to the interleukin 2 receptor.

Despite considerable evidence documenting the central nervous system as a site of immunological privilege, immune responses do occur within the brain and neural allografts between major histocompatibility complexes (MHC) and minor antigen incompatible rat strains may be rejected. The survival of completely MHC incompatible neural allografts has been found to be prolonged indefinitely after administration of a monoclonal antibody (mAb) to the interleukin 2 receptor (IL-2R) for 10 d after transplantation. Here we present evidence that rats with long-term surviving lateral ventricular neural allografts, after anti-IL-2R treatment, accept subsequent neural allografts from the same donor strain, placed in a peripheral nonprivileged site, but rapidly reject third-party grafts. Thus, treatment with a mAb to the p55 chain of the IL-2R has resulted in the specific acceptance of second grafts of fully allogeneic neural tissue. These results suggest that ongoing interaction between elements of the host immune system and alloantigen within the brain maintains the tolerant state and furthermore, that interruption of signaling through the IL-2R may be important in allospecific tolerance induction.

Animals↗
PubMed1993

Cytokines as mediators of organ graft rejection and tolerance.

The analysis of cytokines following organ transplantation continues to flourish as a major area of investigation for transplant biologists. Over the past year many papers have reported the use of both molecular and antibody-based tools to dissect the expression of cytokines during graft rejection in both experimental and clinical transplantation. Further, how the expression of cytokines is altered during the induction of tolerance has been investigated by several groups.

Animals↗
PubMed1993

Analysis of activated T cell infiltrates in rat renal allografts by gamma camera imaging after injection of 123iodine-interleukin 2.

Activated T cells bearing receptors for interleukin 2 (IL-2) play an important role in immunity and in immunopathological processes such as allograft rejection. In order to investigate the presence of activated T cells in lymphocytic infiltrates in transplanted kidneys, we investigated the uptake and retention of radioactivity after an intravenous injection of radioiodinated IL-2 in experimentally transplanted rats. IL-2 was enzyme radiolabelled with 123iodine using a glucose oxidase/lactoperoxidase method and shown to retain specific binding on an IL-2 receptor positive cell line, C58E6. To examine the kinetics of 123iodine-interleukin 2 (123I-IL-2) uptake in vivo, animals that had been transplanted five days previously with allogeneic or syngeneic grafts were injected with 123I-IL-2 and then imaged using an external gamma camera. Radioactivity was measured at time points up to 240 min after intravenous injection of 123I-IL-2. Four groups of animals were examined: allogeneic grafts (n = 7); syngeneic grafts (n = 6); ischaemic native kidneys (n = 5) all following injection with 123I-IL-2; and allogeneic transplants (n = 5) after injection of 123I-lactalbumin, an irrelevant molecule of similar molecular weight to IL-2. The peak radioactivity after injection was measured and the amount of radioactivity retained in the graft at increasing time intervals after injection was expressed as a function of initial peak radioactivity. At four hours after injection of 123I-IL-2, mean retention of activity by rejecting grafts was 77(+/- 2.68)% of peak activity, compared to 45(+/- 6.38)% in syngeneic controls (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Cytokines and peripheral tolerance to alloantigen.

The induction of peripheral tolerance to alloantigen is accompanied in many cases by a decrease in the production of cytokines such as IL-2 and IFN gamma, yet a sustained production of cytokines such as IL-10 and IL-4. Whether or not this altered pattern of cytokine production in tolerant animals is causally related to the induction and/or maintenance of the tolerant state has yet to be fully determined, although experiments blocking selectively the action of IL-2 with CD25 antibodies suggest that manipulation of cytokine production may at least be a route to tolerance. Alternative methods for directly influencing the cytokine balance are sought and recent experiments on the CD28/CTLA-4-B7 interaction suggest a possible approach.

Animals↗
PubMed1992

Characteristics of dogs admitted for treatment of cervical intervertebral disk disease: 105 cases (1972-1982).

Case histories of 105 dogs that were treated for cervical intervertebral disk disease (IVDD) were studied retrospectively. To compare with previous data, dogs were grouped by age, gender, and breed. Dogs were also grouped by clinical signs of disease, and by presence and location of radiologic change. The age range of cases of cervical IVDD was 1 to 13 years (mean, 6.3 years). Fifty-nine percent of dogs treated for cervical IVDD were females, but the proportion of diseased females was similar to females in total hospital admissions. Twenty-eight breeds of dogs were treated for cervical IVDD. Dachshunds and Beagles were significantly over represented (P less than or equal to 0.001). However, gender-breed interaction was not observed. Prevalence of radiologic evidence of disk disease was detected at the following levels of the vertebral column: C2-3, 29%; C3-4, 24%; C4-5, 21%; C5-6, 15%; C6-7, 9%; and C7-T1, 2%. Significant difference was not observed in prevalence of cervical IVDD affecting the first 4 disk spaces. However, prevalence of cervical IVDD at C7-T1 was significantly less than that involving the first 4 disk spaces (P less than 0.02), and the space at C6-7 was significantly less affected than were the first 3 spaces (P less than 0.08). Significant association was not evident between clinical signs (pain and neurologic deficits) and radiologic signs of IVDD, although neurologic deficits were more likely to be observed in association with radiologic signs than with signs of pain.

Age Factors↗
PubMed1992

Disseminated aspergillosis in a dog with diskospondylitis and neurologic deficits.

A German shepherd dog was treated initially for signs of urinary tract infection; subsequently, signs of spinal pain and neurologic deficits developed. Fungal hyphae were found in the urine sediment, and spinal radiography revealed changes in the vertebrae and intervertebral disks at the levels of T3 to T8, T12 to T13, L3-4, and L5-6, consistent with diskospondylitis. Fungal cultures of urine and specimens from spinal lesions yielded Aspergillus terreus. Itraconazole (5 mg/kg of body weight, PO, q 24 h) was used to treat this infection, and locomotion improved. Sudden death occurred 4 weeks after treatment was initiated; this was attributed to exsanguination associated with a weakened renal artery. This dog was raised in Florida and resided in central Virginia. The disseminated aspergillosis found in this dog was not limited to the hot arid climates that some reports suggest are optimal conditions for growth.

Animals↗
PubMed1992

Systemic cytokine response after major surgery.

The systemic cytokine response to major surgical trauma was studied in 20 patients undergoing elective aortic surgery and five patients after inguinal hernia repair. Tumour necrosis factor alpha and interferon gamma were not detected in these patients. An early and short-lived interleukin 1 beta (IL-1 beta) response to major surgery was detected only by intensive sampling in the perioperative period. The IL-1 beta peak preceded a more marked interleukin 6 (IL-6) response that peaked 4-48 h after surgery. IL-6 levels had fallen sharply by 48-72 h in all patients who had an uneventful postoperative course. The IL-6 peaks were significantly lower after hernia surgery than after major aortic operations (P < 0.001); IL-1 beta was not detected in any samples. Three patients undergoing aortic surgery developed unexpected major postoperative complications. IL-6 levels in this group were significantly higher than those of the other patients undergoing aortic surgery within 6-8 h of skin incision, and remained elevated for longer. These rises in plasma IL-6 levels preceded the clinical onset of major complications by 12-48 h. The systemic IL-1 beta and IL-6 response to surgical trauma increased with the severity of the surgical insult. An early, exaggerated IL-6 response was associated with the subsequent clinical development of major complications.

Aged↗
PubMed1992

A monoclonal antibody to the interleukin-2 receptor enhances the survival of neural allografts: a time-course study.

A time-course study of the survival and immunological characteristics of rat neural allografts was undertaken in animals treated with a murine monoclonal antibody to the alpha-chain (p55) of the rat interleukin-2 receptor. This antibody, NDS 63, was administered for ten days following grafting beginning on the day of operation. Inbred rat strains differing at both major and minor histocompatibility loci were selected as donor and host. Furthermore, the recipient strain displayed a high responder major histocompatibility complex haplotype. All grafts were placed in the lateral ventricle. Comparison was drawn between NDS 63-treated recipients and two groups of controls; an untreated group and a second group treated with the monoclonal antibody NDS 66, directed at a second epitope on the alpha-chain of the interleukin-2 receptor, which has been shown to be ineffective in competing with interleukin-2 for binding. Immunocytochemical analysis of the transplants was performed at several time-points up to 150 days following grafting. Grafts of NDS 63-treated recipients exhibited 100% survival with minimal induction of major histocompatibility complex antigens (both class I and class II) and negligible leukocyte infiltration at all time-points studied. In contrast grafts from both groups of controls showed evidence of a chronic immune response with most grafts undergoing rejection as shown by markedly elevated major histocompatibility complex antigen expression accompanied by specific immune cell infiltration. This was a protracted process with several grafts undergoing complete rejection by 60 days and a majority, but not all, by 150 days after transplantation. It is concluded that NDS 63, a monoclonal antibody to the interleukin-2 receptor, may diminish the immune response to transplanted allogeneic neural tissue and thereby enhance its prospects for long-term survival.

Animals↗
PubMed1992

Rectovaginal fistula with atresia ani in three kittens.

Rectovaginal fistula with atresia ani was diagnosed in 3 kittens. Physical abnormalities included abdominal distension, bulging of the perineum, and lack of an anal opening. Vaginography was helpful in determining the type of malformation present in 2 cases. In each kitten attempts were made to surgically correct the anatomic malformations. Various post-operative complications such as fecal incontinence, would dehiscence, constipation, and excessive scar tissue formation occurred and are discussed.

Anal Canal↗
PubMed1991

Cytokine gene transcription in vascularised organ grafts: analysis using semiquantitative polymerase chain reaction.

Cytokine gene transcription has been analyzed by direct analysis of RNA obtained from mouse heterotopic cardiac transplants. The level of expression of the cytokine genes was assessed using semiquantitative polymerase chain reaction (PCR). Expression of the cytokines investigated fell into three groups. The first group included interleukin 1 beta (IL-1 beta), IL-5, IL-6, and interferon gamma (IFN gamma). These genes were expressed in normal heart tissue at low level and were upregulated following both syngeneic and allogeneic transplantation. Genes in the second group (IL-1 alpha, IL-3) were not expressed at detectable levels in normal heart but were induced following either syngeneic or allogeneic heart grafting. IL-2, IL-4, and tumor necrosis factor beta (IFN beta) comprised the third group and these cytokines were expressed only in allogeneic grafts after transplantation.

Animals↗
PubMed1991

Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction.

The expression of 12 cytokine and cytokine receptor genes during mouse thymic ontogeny has been studied using the polymerase chain reaction. The data reveal that IL-2 gene transcription does not begin in the thymus until fetal day (Fd) 16. However, IL-2R beta-chain mRNA was detectable throughout the period of investigation, from Fd 14 to 20. This suggests that the potential for high or intermediate affinity IL-2 binding is present in the thymus before the IL-2 gene is actually expressed. Overall, cytokine gene induction occurred in two distinct patterns. In the first group, represented by IL-1 beta, IL-4, IL-5, IL-6, IL-7, IFN-gamma, and lymphotoxin (lymphotoxin or TNF-beta) there was detectable mRNA present from Fd 14 to 20. IL-1 alpha, IL-2, IL-3, and GM-CSF followed a second pattern in which gene induction was delayed until Fd 16. The expression of IL-7 and IL-2 genes showed an interesting temporal relationship. IL-7 mRNA transcription occurred before IL-2 but diminished from Fd 16 after the onset of IL-2 gene induction. Because these data reflect the in vivo progression of gene expression during T cell ontogeny, they provide a guideline for assessing the physiologic significance of thymocyte responses to cytokines at different stages of fetal development.

Animals↗
PubMed1991

Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway.

Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL-2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL-2 pathway results in tolerance in these alloantigen-treated and transplanted animals.

Animals↗
PubMed1991

Molecular cloning of cDNAs for the rat interleukin 2 receptor alpha and beta chain genes: differentially regulated gene activity in response to mitogenic stimulation.

We have isolated, by transient expression and screening using an oligonucleotide probe, cDNA clones encoding the rat interleukin 2 receptor (IL 2R) alpha and beta chains, respectively. Both chains are approximately 60% identical at the amino acid level to their human counterparts. In common with the human and mouse IL 2R beta chains, the rat beta chain is a member of the cytokine receptor family. The rat IL 2R beta chain contains no conventional signal transduction machinery and, like the mouse IL 2R beta chain, has a significant number of deletions in its cytoplasmic tail in comparison to the human protein. Northern analysis indicates that the rat beta chain message is constitutively transcribed in normal resting lymphocytes, whereas the alpha chain message is absent. Transcription of both chains of the receptor is up-regulated by cellular activation. However, kinetic studies have shown that whereas alpha chain message is rapidly induced, and can be detected 5 h after the addition of phytohemagglutinin, levels of beta chain mRNA increase at a much later time point and are not seen to rise until approximately 24 h after the addition of mitogen. These data suggest that the expression of high-affinity IL 2R is controlled by factors which influence transcription of both the alpha and the beta chain genes.

Amino Acid Sequence↗