Optic neuritis: imaging with magnetization transfer.

OBJECTIVE: Our objective was to prospectively examine the optic nerves in patients with clinically severe unilateral optic neuritis, using routine spin-echo and magnetization transfer MR imaging. SUBJECTS AND METHODS: For 39 patients with such lesions, we calculated the magnetization transfer ratio along the involved intraorbital optic nerve and along the asymptomatic contralateral optic nerve in a mirror-image location. Magnetization transfer ratios were correlated with the imaging findings on routine spin-echo MR imaging. RESULTS: Magnetization transfer ratios were decreased in 33 of the 39 clinically symptomatic optic nerves, including 12 of the 18 clinically symptomatic optic nerves in which no abnormality was seen on routine spin-echo MR images obtained before and after administration of gadopentetate dimeglumine. CONCLUSION: Magnetization transfer imaging reveals intraorbital optic nerve abnormalities in patients with optic neuritis even when such lesions are otherwise occult on routine magnetization transfer imaging.

Selective IL-10 inhibition of HLA-DR expression in IFN-gamma-stimulated human retinal pigment epithelial cells.

PURPOSE: Human RPE cells express HLA-DR antigens, bind leukocytes via ICAM-1, and secrete IL-8 and MCP-1, which attract and activate leukocytes. Since little is known concerning endogenous cytokines that may alter ocular immunologic and inflammatory mechanisms, we investigated whether IL-10, an immunosuppressive cytokine, modulates these HRPE features. METHODS: IL-10 effects on HLA-DR and ICAM-1 were examined by HRPE exposures to: (1) IFN-gamma (10-1000 U/ml) + IL-10 (1-100 U/ml) and (2) IL-10 pre-incubation followed by IFN-gamma + IL-10. Immunohistochemistry for HLA-DR and ICAM-1 was graded by masked observers. Flow cytometric analysis quantitated HRPE HLA-DR and ICAM-1. Effects of IL-10 on IL-1 beta (0.2 or 2 ng/ml)-, or TNF-alpha (0.2 or 2 ng/ml)-induced IL-8 and MCP-1 secretion and gene expression were assessed using enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis. RESULTS: HLA-DR expression, detected by immunohistochemistry and flow cytometric analysis, showed dose-dependent increases to IFN-gamma. IL-10 pre-/co-incubation, but not co-incubation alone, markedly reduced HLA-DR expression, but did not modulate constitutive or IFN-gamma-induced ICAM-1. IL-10 alone did not induce MCP-1 or IL-8 secretion or steady-state mRNA expression, nor modulate IL-1 beta-, TNF-alpha- or IFN-gamma-induced IL-8 or MCP-1. CONCLUSIONS: This study suggests that HRPE HLA-DR antigens are selectively inhibited by IL-10, but the timing of IL-10 exposure may be crucial.

Interleukin-10 inhibition of HLA-DR expression in human herpes stromal keratitis.

PURPOSE: Human herpes stromal keratitis (HSK) is an important cause of visual loss and morbidity. The presentation of corneal and/or viral antigens is thought to activate T lymphocytes, resulting in aberrant cell-mediated immune responses that are central to the pathogenesis of HSK. Aberrant cellular expression of HLA-DR and intercellular adhesion molecule-1 (ICAM-1), both of which are necessary for optimal antigen-induced T-lymphocyte responses, is present in lesions of HSK, but little is known concerning endogenous cytokines that may inhibit HLA-DR or ICAM-I expression in human disease. In this study, the authors investigated the effects of interleukin-10 (IL-10) on HLA-DR and ICAM-1 expression in human HSK. METHODS: Penetrating keratoplasty specimens removed from 5 patients with HSK were divided to provide adjacent sections that were incubated with control medium or the same medium containing IL-10 (100 U/ml) for 48 hours. Immunoperoxidase staining was performed on each control and IL-10-treated corneal specimen to determine HLA-DR and ICAM-1 antigen expression. RESULTS: Interleukin-10 treatment resulted in profound reduction in immunoreactive HLA-DR, but not ICAM-1, in corneal cells and infiltrating leukocytes of all five HSK specimens. CONCLUSIONS: This study suggests that HLA-DR antigens may be selectively inhibited by cytokines released during inflammation in HSK. These results are the first to demonstrate cytokine suppression of HLA-DR in a human disease. Pharmacologic doses of IL-10 may inhibit HLA-DR-dependent immune responses that underlie a variety of destructive ocular inflammatory diseases.

The effect of norepinephrine infusion on oxygen delivery and consumption in the canine model.

Norepinephrine (NE) is used clinically to increase oxygen delivery (DO2) by increasing cardiac output (CO). The rate of administration of NE is usually based on frequent measurements of blood pressure (BP) and infrequent measurements of CO with little regard for oxygen delivery or consumption dynamics. Although the ultimate goal of an inotropic drug is to increase DO2 in excess of metabolic requirements (VO2), the effect of NE on the DO2/VO2 ratio has not been previously studied. In the present investigation, healthy anesthetized dogs were infused with various doses of intravenous NE. These dosages were chosen to span the range used clinically. NE administration caused a significant primary increase in VO2 which was dose dependent (P < 0.001). A similar dose-dependent increase in DO2 was observed (P < 0.001). However, the increase in DO2 minimally exceeded the increase in VO2 at lower doses of NE and the relative increase in VO2 exceeded the change in DO2 at a dose of 0.04 microgram/kg/min. Minimal advantage to oxygen utilization physiology at low doses of NE and a potential deleterious effect at a dose of 0.04 microgram/kg/min were observed, therefore, despite associated increases in mean systemic blood pressure. The effectiveness of NE administration could be most effectively monitored by the mixed venous oxygen saturation (SVO2), rather than by intermittent assessment of BP, CO, or DO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of specific tolerance to class I-disparate renal allografts in miniature swine with cyclosporine.

Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (i.e., ag----ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (i.e., gg----dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, i.v. q.d. for 12 days. This protocol led to the induction of long-term (greater than 100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7 +/- 0.9 days (P less than 0.0001). The specificity of tolerance was assessed both in vivo with subsequent skin grafts and in vitro by mixed lymphocyte response (MLR) and cell-mediated lymphocytotoxicity (CML). Survival of donor-specific skin grafts was prolonged compared with skin grafts bearing third-party class I antigens (19.5 +/- 2.0 versus 11.5 +/- 2.0 days, n = 4, P less than 0.05). Tolerant recipients had markedly diminished or absent anti-donor MLR and CML responses, but maintained normal reactivity to third party. Four of eight CsA-treated recipients showed detectable levels of anti-donor IgM, while none demonstrated the presence of anti-donor IgG, which was found in all rejecting controls.

The failure of skin grafting to break tolerance to class I-disparate renal allografts in miniature swine despite inducing marked antidonor cellular immunity.

Long-term specific tolerance to one haplotype class I plus minor antigen disparate renal allografts develops without exogenous immunosuppression in approximately 35% of miniature swine (n = 128). Previous studies have suggested that this phenomenon is related to limited class I-specific helper T cell activity as evidenced by the failure of antibody class switching in vivo and the ability of exogenous interleukin 2 to elicit antidonor responses in vitro. To determine whether tolerance could be broken by inducing antidonor reactivity with donor antigen and a source of T cell help, multiple skin grafts bearing donor class I plus third-party class II antigens were placed on tolerant animals. Skin grafts were placed at least 3 months after the kidney transplant, at which time all recipients had normal renal function as measured by blood urea nitrogen and serum creatinine. First-set rejection of skin grafts by SLAad and SLAdd hosts occurred in 11.8 +/- 1.1 days (mean +/- SEM, n = 6) and in 9.3 +/- 0.9 days (n = 4), respectively. Coincident with skin rejection, most animals developed a transient rise in BUN to 62 +/- 11 mg/dl (n = 10) and a similar rise in Cr to 4.9 +/- 1.2 mg/dl (n = 10), with normal levels returning in all animals within two weeks. Subsequent skin grafts with the same disparity did not undergo second-set rejection and did not induce BUN or Cr elevations. Prior to skin grafting, animals showed no antidonor activity in mixed lymphocyte reaction or cell-mediated lymphocytotoxicity assays. After two skin grafts, all animals developed donor-specific CML and secondary MLR responses, and additional skin grafts amplified this cellular immunity. Development of marked antidonor immunity without a break in tolerance suggested that either graft adaptation or local suppression might be involved in maintaining tolerance to class I MHC antigens. In preliminary studies, an immunized SLAad animal and an immunized SLAdd animal were retransplanted with kidneys MHC matched to their first allografts. In both cases, the second graft was accepted permanently without immunosuppression, suggesting that graft adaptation is not necessary for the maintenance of tolerance to renal allografts in miniature swine.

Prostaglandin E2 inhibits in vitro and in vivo lymphocyte responses in allogeneic transplantation.

Prostaglandin E2 (PGE2) has been shown to a clear role in the suppression of immune responses after burn and trauma injury. This probably results from inhibition of interleukin-2 production. This study examined the effects of PGE2 in vivo on the survival of solid-organ allografts and in vitro on the rat allogeneic mixed lymphocyte response. Administration of 16,16-dimethyl prostaglandin E2 (DMPGE2), a stable analogue of PGE2, significantly prolonged the survival of heterotopic cardiac allografts from ACI to LBN rats: 10.4 +/- 1.7 days versus 5.7 +/- 1.1 days (mean +/- standard error of the mean) (p less than or equal to 0.001). In 1 animal, DMPGE2 apparently led to the induction of long-term tolerance. Mixed lymphocyte cultures using splenocytes from naive LBN and ACI rats to which DMPGE2 was added showed a dose-dependent suppression of the mixed lymphocyte response with concentrations as low as 1 x 10(-7) mol/L. Splenocytes harvested from treated animals with functioning but histologically rejecting hearts demonstrated a marked decrease in mixed lymphocyte response to donor (ACI) stimulators compared with naive LBN controls (3,804 +/- 603 versus 27,395 +/- 2,668 cpm, n = 4), but maintained a normal response to third-party (Wistar Furth) stimulators. We conclude that DMPGE2 suppressed solid-organ allograft rejection, inhibited the allogeneic mixed lymphocyte response, and induced donor-specific in vitro hyporesponsiveness.

Using helium-oxygen mixtures in the emergency management of acute upper airway obstruction.

Helium (80%)-oxygen (20%) mixtures (He-O2) are less dense and less viscous than room air. Respiratory work to overcome upper airway obstruction from a number of pathologic conditions may be reduced by inhaling He-O2 instead of room air. We present the case of a 23-year-old woman with a history of asthma and tracheal angioedema refractory to conventional antiasthma and even immunosuppressive therapy. She had previously required frequent intubation and mechanical ventilatory support. During the most recent episode of respiratory distress, prior to intubation as access for mechanical ventilatory support, the patient was placed on He-O2 by a nonrebreathing face mask. She improved clinically within minutes, and continuous pulse oximetry showed a rise in oxygen saturation from 91% to 98%. The patient's condition stabilized and intubation was not required during the subsequent hospitalization. He-O2 may be beneficial in certain patients with acute upper airway obstruction as a noninvasive, temporizing therapy with minimal adverse effects. We recommend close monitoring of the clinical response and the use of continuous pulse oximetry, substantiated by arterial blood gases when feasible.