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J Shelby

Publications and source records attributed to J Shelby.

At least 37 records · Page 2Linked to original sources
PubMed1993

Immunomodulation in vivo by the Mycoplasma arthritidis superantigen, MAM.

Mycoplasma arthritidis produces a potent superantigen (MAM) that activates specific murine and human T lymphocytes to proliferate and secrete lymphokines. We show here that MAM also influences both T- and B-cell functions in vivo. Lymphocytes from mice injected with MAM exhibit a suppression of proliferative responses to MAM in vitro but only a partial suppression of responses to other mitogens. This T-cell anergy not only decreased contact sensitivity to dinitrofluorobenzene but also prolonged survival of skin transplants. In contrast, B-cell reactivity is increased following in vivo injection of MAM, as evidenced by enhanced antibody responses to sheep red blood cells and ovalbumin. Also, there is a marked decrease in the ability of splenocytes from MAM-injected mice to produce interleukin-2 (IL-2) but a marked increase in their ability to produce IL-4 and IL-6. The combined results suggest that MAM induces a lymphokine profile that favors activation of B-cell functions, with a resulting potential for triggering of autoimmune disease.

Acquired Immunodeficiency Syndrome↗
PubMed1993

The effect of cyclosporine treatment on the expression of genes encoding granzyme A and perforin in the infiltrate of mouse heart transplants.

Following activation of cytotoxic T cells and NK cells several genes encoding proteins putatively involved in cell-mediated cytotoxicity become expressed. The expression of genes encoding the cytotoxic T cell associated serine protease granzyme A and perforin was analyzed in cellular infiltrates of MHC mismatched (H-2d-->H-2k) heterotopic heart transplants both in immunosuppressed recipients treated with cyclosporine and in untreated recipients. Heart transplants were completely rejected by untreated animals on day 10 post-transplantation, whereas CsA treatment generally prolonged survival of the transplants beyond 30 days. In untreated recipients the number of granzyme A- and perforin-expressing cells in heart transplants increased from approximately 10 granzyme A-positive cells/mm2 and 1 perforin-positive cell/mm2 on day 2 posttransplantation to over 80 positive cells for both genes on day 5 posttransplantation. In contrast, these values remained always below 15 positive cells/mm2 for both genes between day 5 and day 30 posttransplantation in CsA-treated recipients. Comparison of the frequency of CD8+ T cells in the infiltrates showed that lower numbers of perforin and granzyme A-positive cells were mainly due to the immunosuppressive action of CsA rather than to reduced infiltration of transplants. The present study shows that expression of granzyme A and perforin gene can be used to discriminate between quiescent and activated cytotoxic cells also in immunosuppressed animals and further confirms that these can be used as sensitive markers for monitoring the fate of a transplant.

Animals↗
PubMed1993

Accelerated rejection of murine cardiac allografts by murine cytomegalovirus-infected recipients. Lack of haplotype specificity.

Clinical studies have revealed a correlation between cytomegalovirus (CMV) infection and acute allograft rejection. Likewise, for a murine model we observed that C3H (H-2k) recipients infected with murine CMV (MCMV) rejected BALB/c (H-2d) cardiac allografts earlier than uninfected recipients (6.9 +/- 0.1 d compared with 8.1 +/- 0.6 d; P < 0.001). It has been hypothesized that MCMV epitopes crossreact with alloantigens and in this manner induce rejection. However, we also demonstrated that MCMV caused accelerated rejection in the reverse combination (C3H heart engrafted to BALB/c recipient; 7.2 +/- 0.3 and 9.4 +/- 0.4 d for infected and control animals, respectively; P < 0.001) and accelerated rejection of grafts of a third, unrelated haplotype (C57Bl/6; H-2b; 8.0 +/- 0.7 d compared with 10.1 +/- 0.6 for infected and control C3H recipients, respectively; P < 0.03). Ultraviolet (UV) inactivation of MCMV before administration to the graft recipient abrogated the ability to induce rapid rejection. Activated T lymphocytes were present in grafts from infected recipients 2 d before control recipients (P < 0.02) and, at the time of graft rejection, were almost exclusively CD8+ for both infected and control recipients. Thus, MCMV accelerated rejection appears not to result from crossreaction between MCMV epitopes and MHC products. The failure of UV-inactivated virus to accelerate rejection and the high proportion of CD8+ T cells recovered from all rejected grafts suggest that the class I pathway of antigen presentation may be important in the induction of early rejection.

Animals↗
PubMed1992

Noninvasive assessment of metabolism in wounded skin by 31P-NMR in vivo.

Phosphorus-31 nuclear magnetic resonance techniques using shallow penetrating coils have been used to noninvasively monitor severity and metabolic changes over time in skin wounds in rats. Ratios of phosphocreatine (PCr) to inorganic phosphate (Pi) indicate energy status in both thermal wounds and surgical flaps. In partial and full-thickness scald wounds, reductions in PCr/Pi ratios correlated with burn depth and improved over time postinjury, suggesting wound revascularization. No decrease in intracellular pH was noted in these wounds; the phosphate shifts may be primarily the result of tissue degradation followed by restoration of the microvasculature. Distal regions of caudally based dorsal 3 x 10 cm full-thickness skin flaps reveal progressively lower PCr/Pi ratios to 3-6 hours after elevation as well as drops in pH up to 0.5 units, presumably as a result of anaerobic glycolysis in these tissues. After 24 hours, the intracellular pH returned to normal (7.1-7.2) and the PCr/Pi ratios approached 70%-90% of the well-perfused proximal regions within 3-7 days. These results indicate the establishment of a microvasculature from the underlying bed as the distal regions survive as free grafts. The data demonstrate the potential usefulness of the technique in noninvasive measurement of the biochemical response to injury and wound healing in living organisms.

Animals↗
PubMed1992

Mobilization of T lymphocytes following cardiac transplantation. Evidence that CD4-positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration, and acute allograft rejection.

Modified limiting dilution analysis (LDA) techniques were used to evaluate the mobilization of antigen-stimulated helper T lymphocytes (HTL) and cytotoxic T lymphocytes (CTL) following allogeneic heterotopic cardiac transplantation. These modified LDA techniques allow a quantitative comparison of T cells that have been stimulated by antigen in vivo versus unstimulated precursor T cells of the same antigen specificity. Endothelial changes associated with mononuclear cell infiltration of the transplant were studied using endothelia-specific monoclonal antibodies and immunohistochemistry. Early (day 3) infiltration of cardiac allografts was characterized by a prevalence of donor alloantigen-specific HTL over CTL. Immunohistology revealed that the day-3 infiltrate was associated with areas of differentiated vascular endothelium, located primarily in the subepicardial region. Though donor-specific precursor HTL and CTL were present in the peripheral lymphoid tissues and blood, very few of them had been stimulated at this early time. During the latter phases of the response (days 6-9), antigen-stimulated HTL and CTL were present in the rejecting heart with CTL dominating the response. Accumulation of large numbers of donor-specific CTL in the allograft correlated with extensive inflammatory endothelial development, myocyte destruction, and loss of graft function by day 9. Stimulated HTL and CTL were detectable in peripheral lymphoid tissues at days 6 and 9. In addition, a marked increase in the number of donor-specific precursor CTL, but not precursor HTL, was observed in the lymphoid tissues at the peak of the response. Depletion of class II MHC-restricted T cells by in vivo treatment with anti-CD4 mAb eliminated HTL activity in all lymphoid compartments assessed and markedly reduced the number of CTL infiltrating the allograft. In addition, no stimulated CTL were detectable in lymphoid tissues, and the number of precursor CTL was not increased. In anti-CD4-treated recipients, cardiac allografts remained functional with minimal histological evidence of rejection for at least 21 days. Though graft-associated inflammatory endothelia were absent in anti-CD4-treated recipients at day 6, endothelial differentiation was observed in day 21 allografts in anti-CD4-treated recipients. These observations indicate that inflammatory endothelial development may precede T cell infiltration and subsequent loss of the cardiac allograft function. Thus, CD4-positive HTL are required for (1) graft-associated inflammatory endothelial development; (2) CTL activation in peripheral lymphoid tissues; (3) CTL accumulation in allografted tissues; and (4) acute cardiac allograft rejection.

Animals↗
PubMed1991

Expression of the protease gene HF as a marker in rejecting allogeneic murine heart transplants.

Phenotypic characterization of the inflammatory infiltrate often provides very little information about the fate of a transplant. Therefore we decided to look for functional markers, characteristic for activated effector cells involved in the rejection of primarily vascularized MHC-mismatched heart transplants in mice. Infiltrating cells in the interstitium of eventually rejected allogeneic heart transplants were found to express the gene for the serine esterase HF (granzyme A) in high numbers already on day 2 following transplantation, whereas HF mRNA positive cells were absent, or only rarely found, in syngeneic nonrejecting transplants throughout the entire observation period of 10 days after transplantation. These findings could also become of importance for the prediction of the outcome of organ transplants in humans.

Animals↗
PubMed1991

Intraperitoneal sensitization and the transplanted mouse heart.

Intradermal or skin-graft sensitization always results in accelerated rejection of subsequent MHC-disparate mouse heart transplants; intravenous or intrasplenic sensitization almost always results in prolonged survival. The survival time after intraperitoneal sensitization is unpredictable: hyperacute or accelerated rejection, as well as normal or prolonged survival, occurs suggestive of a delicate balance between suppressive and rejecting immune responses. We have observed a positive correlation between transplant survival and the distribution of 51Cr-labeled antigenic cells early after i.v., i.d., i.p., and intrasplenic injection. Label recovery from the viscera was already high 2 hr after i.v. injection, while after i.d. injection virtually all label was still confined to the carcass, even at the end of a 24-hr period. After i.p. injection label recovery varied significantly from mouse to mouse, from very low to a level approximating that seen after i.v. injection. This close correlation suggests that the fate of a subsequent transplant is decided within a few hours after antigen deposition, well before placement of the transplant itself.

Animals↗
PubMed1991

The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy.

The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.

Animals↗
PubMed1991

Myocyte injury and contraction abnormalities produced by cytotoxic T lymphocytes.

BACKGROUND: The mechanisms by which ventricular function is altered during cardiac transplant rejection are not well understood. Therefore, an in vitro model system has been developed to facilitate investigation of lymphocyte-mediated myocyte injury. METHODS AND RESULTS: Splenic lymphoid cells were obtained from mice 8-10 days after placement of a vascularized abdominal cardiac allograft and were restimulated in vitro with irradiated donor-type splenocytes for 5 days. Cytotoxic effects of these allogenically stimulated lymphocytes on syngeneic and donor strain fetal cultured myocytes were determined by a 51Cr release assay at different lymphocyte to myocyte ratios. 51Cr release from donor strain myocytes was detectable within 1 hour of exposure, was maximal by 3-5 hours of coincubation with sensitized lymphocytes, and was allospecific. Cell injury manifest by 51Cr release was calcium dependent and was inhibited by pretreatment of lymphocytes with phorbol ester to deplete protein kinase C. Myocyte injury was also prevented by pretreatment of sensitized lymphocytes with anti-Thy 1.2 or anti-CD8 antibody plus complement but not by treatment with anti-CD4 antibody, indicating that CD8+ cytotoxic T cells are involved. Altered myocyte contractile motion preceded myocyte lysis (51Cr release), was characterized by an initial reversible decrease in amplitude of contraction, and was followed by rapid and irregular beating with eventual complete cessation of contraction. Contractile alterations induced by sensitized lymphocytes were inhibited by elimination of CD8+ cells. CONCLUSIONS: Myocyte injury can be produced by sensitized cytotoxic T lymphocytes in vitro and is calcium and protein kinase C dependent. The contractile abnormalities produced appear to be similar to those observed in cardiac transplant patients undergoing rejection, and thus this model system promises to allow investigation of the mechanisms involved.

Abdomen↗
PubMed1990

The slotted crossover surface coil: a detector for in vivo NMR of skin.

An elongated, narrow, slotted crossover surface coil provides surface localization capable of resolving in vivo 31P NMR spectra from skin tissues. The shallow B1 field penetration achieves localization objectives while the probe length maintains signal-to-noise requirements. Dielectric and inductive losses are minimized via the crossover design (see T. L. Nagel et al., Magn. Reson. Med. 13, xxx (1990). In vivo spectra with millimeter depth resolution were acquired in 5 min at 2 T without pulse localization sequences. Preliminary 31P NMR spectra of normal and thermally injured rat skin were completed using a 25 X 3-mm slotted probe with a 3 X 2-cm surface region of excitation. Normal rat skin tissue PCr/Pi ratios ranged from 3.8 to 4.7 for 5-, 10-, and 30-mus pulse widths, while partial- and full-thickness scald injured tissues ranged from 0 to 2.8. Evaluation of a single minor partial thickness injury 1 to 5 h postburn shows evidence of a localized hypermetabolic response associated with hyperemia. Determination of burn depth and tissue viability appears feasible using: (1) PCr/Pi ratios and (2) observation of localized hypermetabolism.

Animals↗
PubMed1990

The continuing challenge of burn care in the elderly.

Recent improvements in survival have stimulated interest in the care of elderly patients with burn injuries. We reviewed 278 patients aged 45 years and older treated during a 10-year period. The survival rate was 80% overall and 67% for patients over 75 years of age. Mortality rates correlated with patient age, burn size, presence of inhalation injury, number of complications of care, and fluid resuscitation requirements, but not with the number of preexisting medical problems. Burn wound excision and skin grafting were performed frequently and were well tolerated. During this period, hospital charges increased fourfold and were twice as great in nonsurvivors. Reimbursements based on diagnosis-related groups during the last 3 years of the review (75 patients) resulted in a total deficit of $1.2 million. Aggressive care for most elderly patients with burn injuries appears justified by the improved outcomes demonstrated. This has increased the difficulty of decisions regarding patient salvability and the allotment of resources. Elderly patients with burn injuries illustrate many contemporary dilemmas in patient care in this era of cost consciousness.

Aged↗
PubMed1989

Hyperacute rejection of the transplanted mouse heart.

Mouse hearts transplanted heterotopically to MHC-disparate recipients can be hyperacutely rejected (HAR) after a single or 3 sequential donor type skin grafts, or a single intradermal injection of lymphoid cells. In the combinations tested, not all hearts are HAR; most of them are rejected in accelerated fashion. Our results with transplanted rat hearts are similar, even in a genetic combination for which HAR of all hearts has been reported. However, in rats, HAR tends to occur more rapidly and to be associated with more-intense vascular changes. Transfer of serum from mice or rats sensitized by 3 sequential skin grafts likewise resulted in occasional hyperacute but never accelerated rejection. Transfer of lymph node cells from mice sensitized with a single skin graft always resulted in accelerated but never in hyperacute rejection; transfer of cells after 3 sequential skin grafts caused neither accelerated nor hyperacute rejection.

Acute Disease↗
PubMed1988

Effect of ibuprofen and interleukin 2 on transfusion-induced suppression of cell-mediated immunity.

Transfusion-induced immunosuppression has been associated with excessive production of prostaglandin E and decreased interleukin 2 (IL-2) production. In the present study, allogeneic blood-transfused mice were tested for cell-mediated immunity with the use of a delayed-type hypersensitivity assay. In vivo administration of a cyclo-oxygenase inhibitor, ibuprofen, and murine recombinant IL-2 was initiated on day 0 and continued daily throughout the delayed-type hypersensitivity assay. The results indicate that prostaglandin E may play a primary role in allogeneic blood transfusion-induced suppression, as manifest by normal responses in ibuprofen-treated mice. Supplementation of transfused mice with recombinant IL-2 also preserved immune response, indicating inadequate IL-2 production after transfusion, while receptor expression appears to remain intact.

Animals↗