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Biomedical subjects

Z D Ling

Publications and source records attributed to Z D Ling.

At least 19 recordsLinked to original sources
PubMed1999

Animal model of posthypoxic myoclonus: effects of serotonergic antagonists.

OBJECTIVE: To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus. BACKGROUND: Although serotonergic system dysfunction is implicated in posthypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated. METHODS: The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at -30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six doses across a range from the original dose studied to 10% of that dose. RESULTS: Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose-response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. CONCLUSIONS: 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance-Adams syndrome.

Acoustic Stimulation↗
PubMed1999

Cytokine-induced conversion of mesencephalic-derived progenitor cells into dopamine neurons.

We have previously shown that a combination of the cytokines interleukin (IL)-1, IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF) can convert rat fetal (E14.5) mesencephalic progenitor cells into tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in vitro. The experiments described here characterize the mesencephalic progenitor cells and their cytokine-induced conversion into dopamine (DA) neurons. For all experiments, we used bromodeoxyuridine (BrdU)-ir cultures of (E14.5) mesencephalic progenitor cells that had been expanded at least 21 days. We first demonstrated that IL-1 induced DA neuron conversion in mesencephalic progenitors, but not in striatal progenitors (P < 0.001). Thus, these cells should be classified as lineage-restricted progenitors, and not omnipotent stem cells. To further characterize cell populations in these cultures, we used monoclonal antibodies against Hu (an early marker for neurons), growth-associated protein (GAP)-43 (a marker for neuronal process extension), TH (a marker for DA neurons), and glial fibrillary acidic protein (GFAP, a marker for astrocytes). We assessed (E14.5) mesencephalic progenitor cell cultures (plated at 125,000 cells/cm2) incubated in the cytokine mixture (described above) or in complete media (CM, negative control). Following 7 days incubation, GFAP-positive cells formed a nearly confluent carpet in both types of cultures. However, numbers of Hu-ir and GAP-43-ir cells in the cytokine-incubated cultures far exceeded those in CM-incubated controls (P = 0.0003, P = 0.0001, respectively), while numbers of TH-ir cells were 58-fold greater in the cytokine-incubated cultures versus CM-incubated controls. The TH phenotype persisted for 7 days following withdrawal of the differentiation media. Numerous double-labeled cells that were BrdU-ir and also TH-ir, or Hu-ir and also TH-ir, were observed in the cytokine-incubated cultures. These data suggest that cytokines "drive" the conversion of progenitor cells into DA neurons.

Animals↗
PubMed1999

Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures.

Pramipexole (PPX) is a full intrinsic activity, direct-acting dopamine (DA) agonist possessing 7-fold higher affinity for D3 than for D2 receptors. It also is a potent antioxidant. PPX was previously shown to be neuroprotective because it dose dependently attenuated the DA neuron loss produced by levodopa in mesencephalic cultures. Several different drugs with properties similar to PPX were studied here to better understand the mechanism or mechanisms responsible for this neuroprotective effect. The D3-preferring agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D3 antagonist U99194, respectively, increased and decreased the neuroprotective effects of PPX in a dose-dependent fashion. Addition of the selective D2 agonist U95666 or the D2/D3 antagonists domperidone or raclopride did not affect PPX's neuroprotective effect. Interestingly, 7-OH-DPAT by itself did not attenuate the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was combined with a low dose of the antioxidants U101033E or alpha-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed when the D3-preferring agonist PD128, 907 was studied. In addition, media conditioned by exposure of mesencephalic cultures incubated with all D3-preferring agonists studied was shown to enhance the growth of DA neurons in freshly harvested recipient cultures implicating a D3-mediated trophic activity in the neuroprotective effect. These data suggest that PPX's neuroprotective actions in the levodopa toxicity model are a consequence of its combined actions as a D3 receptor agonist and an antioxidant.

Animals↗
PubMed1998

Partial purification of a pramipexole-induced trophic activity directed at dopamine neurons in ventral mesencephalic cultures.

We previously demonstrated that media conditioned by exposure to ventral mesencephalic (VM) cultures in the presence of pramipexole (PPX) and other drugs with dopamine (DA) D3 properties, increased the growth and survival of DA neurons in recipient VM cultures. This trophic activity was heat-labile and not present in parietal cortex cultures or cultures pretreated with the DA neuron toxin MPP+. In an effort to begin to identify the protein(s) responsible for this trophic effect, we compared the conditioned media from normal VM cultures, VM cultures incubated with PPX, and VM cultures pretreated with MPP+ and treated with PPX. Neutralization studies using anti-GDNF and anti-BDNF failed to reduce the conditioned media transfer effect, and Millipore Ultrafree centrifugation studies placed the mol.wt. of the activity around 30 kDa. SDS separation revealed three potential bands of interest. A 35-kDa band was present in normal cultures, increased in PPX-incubated cultures, and absent in MPP+-pretreated/PPX-incubated cultures. This conforms to the effect the protein concentrates used to produce these gels had on the growth of DA neurons in VM cultures. Since VM cultures grown in neural basal media, which inhibits the growth of glia, still responded to PPX in a dose-dependent fashion, the trophic activity may be a DA autotrophic factor. However, the gels also revealed two bands at approximately 31 and 55 kDa that were reduced by exposure to PPX and present in MPP+-pretreated cultures. The possibility that these are neuroinhibitory factors that are also regulated by PPX therefore cannot be ruled out.

Animals↗
PubMed1998

Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines.

Rat progenitor cells from the germinal region of the fetal mesencephalon were isolated and expanded in media containing the mitogen epidermal growth factor. These cells remained mitotically active (up to 8 months), were immunoreactive for the progenitor cell marker nestin, and were readily infected with the BAG alpha retrovirus. When incubated in complete media containing serum in poly-L-lysine-coated plates, these cells spontaneously converted to neurons and glia but rarely expressed the dopamine (DA) neuron phenotype. Nineteen different cytokines were screened for their ability to induce the DA phenotype and only interleukin (IL)-1 was found to induce the expression of the DA neuron marker tyrosine hydroxylase (TH). The addition of IL-1, IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF) were found to further increase the number of TH immunoreactive (TH-ir) cells. The addition of mesencephalic membrane fragments and striatal culture-conditioned media along with the cytokine mixture induced the expression of morphologically mature TH-ir cells that were also immunoreactive for dopa-decarboxylase, the DA transporter, and DA itself. The DA neuron cell counts were approximately 20-25% of the overall cell population and 50% of the neurofilament population. Astrocytes and oligodendrocytes were also present. These data suggest that hematopoietic cytokines participate in the development of the DA neuron phenotype. Parallels between the function of hematopoietic cytokines in bone marrow and the central nervous system may exist and be useful in understanding the factors which regulate the differentiation of neurons in the brain.

Animals↗
PubMed1998

Peptide inhibitors of caspase-3-like proteases attenuate 1-methyl-4-phenylpyridinum-induced toxicity of cultured fetal rat mesencephalic dopamine neurons.

Multiple aspartate-specific cysteine proteases have been identified and specific members of this family have been implicated in the apoptotic death of many mammalian cell types. Caspase-3-like proteases seem to play a pivotal role in neuronal apoptosis since mice with germline inactivation of the caspase-3 gene manifest profound alterations in neurogenesis. Moreover, inhibitors of caspase-3-related proteases have been shown to inhibit neuronal apoptosis. Here we extend recent work from our laboratory on the mechanisms mediating the neurotoxic actions of 1-methyl-4-phenylpyridinium using ventral mesencephalon cultures containing dopamine neurons. We demonstrate that low concentrations of 1-methyl-4-phenylpyridinium induce apoptosis in dopamine neurons by morphological and biochemical criteria. Moreover, pretreatment of ventral mesencephalon cultures with the tetrapeptide inhibitors of the caspase-3-like proteases zVAD-FMK or Ac-DEVD-CHO specifically inhibit death of dopamine neurons induced by low concentrations of 1-methyl-4-phenylpyridinium, whereas the caspase-1-like inhibitor Ac-YVAD-CHO was without effect. Our data indicate that exposure of cultured ventral mesencephalon dopamine neurons to low concentrations of 1-methyl-4-phenylpyridinium results in apoptotic death and that caspase-3-like proteases may mediate the neurotoxic apoptotic actions of 1-methyl-4-phenylpyridinium.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Intravenous levodopa in hallucinating Parkinson's disease patients: high-dose challenge does not precipitate hallucinations.

In five nondemented Parkinson's disease patients with daily visual hallucinations, we tested whether high-dose IV levodopa (LD) infusions precipitated hallucinations. Two infusion paradigms were studied, each with 1.5-mg/kg hourly dose for 4 hours--steady infusion and pulse infusion of the full hour dose over 5 minutes each hour. In both protocols, plasma LD levels changed significantly during the infusion protocol. The cumulative area under the curve was equivalent for the two infusions. All patients remained alert, and none developed visual hallucinations. The two patients with peak-dose dyskinesias on oral LD developed prominent dyskinesias during the infusion. Visual hallucinations do not relate simply to high levels of LD or to sudden changes in plasma levels.

Aged↗
PubMed1997

Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole.

The direct-acting dopamine (DA) agonist pramipexole (2 amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochlori de) was evaluated for its ability to attenuate levodopa-induced loss of tyrosine hydroxylase immunoreactive (THir, a marker for dopamine neurons) cells in mesencephalic cultures. Pramipexole reduced levodopa-induced THir cell loss in a dose-dependent and saturable fashion (ED50 = 500 pM), its inactive stereoisomer was significantly less potent in this regard and pergolide and bromocriptine had negligible cytoprotective effects. Culture media from mesencephalic cultures incubated with pramipexole for 6 days increased THir cell counts in freshly harvested recipient cultures. The magnitude of this effect was directly proportional to the amount of pramipexole in the donor cultures and heat-inactivation of the media abolished the growth promoting effect. The results from this exploratory set of experiments suggest that pramipexole may be cytoprotective to dopamine neurons in tissue culture. Pramipexole's affinity for DA receptors, its antioxidant action or its ability to enhance mesencephalic trophic activity could be responsible for this effect.

Animals↗
PubMed1996

Loss of striatal DA innervation increases striatal trophic activity directed at DA neurons in culture.

Male rats received intraventricular infusions of the dopamine (DA) neurotoxin 6-hydroxydopamine (6-OHDA; 0, 75, 150, and 250 micrograms) in order to determine if DA neuron loss was associated with an increase in striatal trophic activity. After 4 weeks, the animals were sacrificed and perfused with normal saline, and the brains were removed, immediately frozen, and processed. Intraventricular infusions of 6-OHDA were associated with a dose-dependent reduction in striatal DA content and tyrosine hydroxylase-immunoreactive (THir) cell counts in the substantia nigra while striatal DA activity ([HVA]/[DA]) was increased. Extracts of the striatum from these animals increased the survival of E15 primary, dissociated rostral mesencphalic cultures growing at low cell density. This growth effect was positively correlated with the dose of 6-OHDA infused. THir cell counts present in high-cell-density mesencephalic cultures following 72 h of extract incubation were similarly correlated to 6-OHDA dose but inversely correlated with striatal DA content and THir cell counts in the substantia nigra. Trophic activity in the cerebellar extracts from these animals was significantly lower than that present in striatal extracts and was not influenced by 6-OHDA lesions. These data suggest that loss of DA innervation in the striatum is associated with an increase in striatal trophic activity directed at DA neurons. A compensatory response to the loss of DA neurons involving increased striatal trophic activity may result in increased DA terminal sprouting of remaining viable DA neurons that, in turn would serve to help reinstate normal DA tone.

Animals↗
PubMed1996

Comparison of the neurotoxicity of dihydroxyphenylalanine stereoisomers in cultured dopamine neurons.

Oxidant stress resulting from excess dopamine (DA) may contribute to the development and progression of Parkinson's disease (PD). Free radicals resulting from the enzymatic metabolism of DA are most often discussed in this regard. However, levodopa (L-DOPA) and DA can also undergo autooxidation, producing free radicals as well as cytotoxic metabolites. We evaluated the neurotoxic effects of the two stereoisomers of L-DOPA to differentiate between enzyme-mediated and autooxidation mechanisms. Various concentrations of D- or L-DOPA (1 mM through 10 nM) were added to freshly harvested rostral mesencephalic tegmentum cultures. After 72 h, the cultures were fixed and stained for tyrosine hydroxylase (TH). The number of TH-immunoreactive (THir) neurons was then assessed and used as an index of DA neuron survival. Both D- and L-DOPA induced a dose-dependent loss of THir neurons (F10,21 = 135.75, p < 0.0001 and F10,21 = 142.53, p < 0.0001, respectively) with ED50 values of 10(-5.3) and 10(-5.2) M, respectively. The dose-response curves for each drug were not significantly different from one another (F1,43 = 0.09, p > 0.05). Moreover, both drugs killed THir as well as non-THir cells at high concentrations, suggesting a nonspecific toxic effect. These data are most consistent with an enzyme-independent, autooxidation-mediated mechanism for DA neuron loss.

Animals↗
PubMed1996

Alpha-tocopherol in the ventricular cerebrospinal fluid of Parkinson's disease patients: dose-response study and correlations with plasma levels.

OBJECTIVE: To determine if ventricular cerebrospinal fluid (vCSF) alpha-tocopherol levels in Parkinson's disease (PD) patients can be increased by oral alpha-tocopherol supplementation and whether vCSF levels are linearly related to plasma alpha-tocopherol levels. BACKGROUND: In spite of its putative neuroprotective properties, alpha-tocopherol has failed to alter PD clinical progression. However, the ability of supplemental alpha-tocopherol to affect brain or vCSF levels has never been assessed in humans nor has a dose response curve for alpha-tocopherol in vCSF been established. METHODS: Five PD patients with Ommaya catheters received oral dl-alpha-tocopherol over 5 months. Each patient ingested alpha-tocopherol daily with monthly dosage increases (400, 800, 1,600, 3,200, 4,000 IU/day). Plasma and vCSF samples were obtained at baseline and at the end of each month. Alpha-tocopherol levels were determined in triplicate by high-pressure liquid chromatography with fluorometric and electrochemical detection. RESULTS: At baseline, endogenous alpha-tocopherol was detected in plasma and vCSF, with a greater than one-hundred-fold difference between the fluid compartments (mean plasma level 18.76 microM/l (SD +/- 4.69) versus mean CSF level 0.114 microM/l (SD +/- 0.084). A clear dose-response curve occurred in plasma, with statistically significant increases over baseline developing even with 400 IU/d. With higher doses, a significant increase continued without evidence of saturation. However, there was no significant increase in vCSF alpha-tocopherol levels at any dose, including the supraclinical (4,000 IU/d). There was no correlation between plasma and vCSF alpha-tocopherol levels. CONCLUSION: Oral alpha-tocopherol supplementation, even at supraclinical doses, fails to increase vCSF alpha-tocopherol levels. This lack of change may be due to limited passage across the blood-brain barrier or very rapid alpha-tocopherol metabolism. All prior negative studies on efficacy of alpha-tocopherol in PD may need reevaluation in light of these pharmacologic data.

Dose-Response Relationship, Drug↗
PubMed1996

Liquid levodopa/carbidopa produces significant improvement in motor function without dyskinesia exacerbation.

We performed the first double-blind, crossover comparison between levodopa/carbidopa (LD/CD) in optimized liquid versus tablet doses to measure plasma LD levels and relative effects on disabilities (motor function, fluctuations, and dyskinesias) in patients with Parkinson's disease. Twenty-three subjects with motor fluctuations were optimized with open-label LD/CD tablets and liquid. In a double-dummy design, patients randomly received 2 weeks of liquid and 2 weeks of tablet LD/CD. Twice during each arm, we evaluated patients hourly 9 AM to 4 PM with the use of plasma LD levels, the Unified Parkinson's Disease Rating Scale, a dyskinesia rating scale, and "on-off" ratings. Patients receiving liquid LD/CD ingested significantly higher doses and had significantly improved motor function and total "on" time, without an increase in dyskinesia severity. The number of motor fluctuations in the two phases was not significantly different. LD levels and variability were also equivalent with the two formulations. At optimized dosing, liquid LD/CD offers a means to significantly improve motor disability in patients with Parkinson's disease without exacerbating dyskinesia.

Adult↗
PubMed1994

Production of factors with B-cell growth and differentiation activities by peripheral blood mononuclear cells from patients with hypogammaglobulinemia.

BACKGROUND: The maturation of normal B lymphocytes proceeds through a growth phase and a differentiation phase. These two phases appear to be under the influence of mediators released by immune cells, B-cell growth factor(s), which induce proliferation of B cells; and B-cell differentiation factor(s), which induce B-cell differentiation. METHODS: We analyzed the ability of peripheral blood mononuclear cells from patients with hypogammaglobulinemia to produce B-cell growth factor and B-cell differentiation factor activity in comparison with normal peripheral blood mononuclear cells. RESULTS: Of 27 patients tested, 26 had normal production of B-cell growth factor activity. A quantitative but not absolute defect in B-cell growth factor production was demonstrable in one boy with hypogammaglobulinemia. Interleukin-2 and interleukin-4 levels, as determined antigenically in these supernatants, had a similar distribution pattern from patients' or from control peripheral blood mononuclear cells; that is, undetectable levels of interleukin-2 were produced by cells from 4 of 16 patients tested and from 4 of 13 control subjects, and undetectable levels of interleukin-4 produced by cells from 6 of 16 patients and 4 of 13 control subjects. B-cell differentiation factor activity was absent in only one child tested but present in all other patients. Two patients had quantitatively low secretion of B-cell differentiation factor, but all others were within normal range. The two patients with quantitatively depressed B-cell differentiation factor activity had normal levels of B-cell growth factor activity, interleukin-2, and interleukin-4 produced from their cells. CONCLUSION: Peripheral blood mononuclear cells from the majority of patients with hypogammaglobulinemia appear to have the capacity to produce B-cell growth factors and B-cell differentiation factor activity in vitro.

Adolescent↗
PubMed1993

Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo.

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytes in vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-gamma was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-gamma levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-gamma. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-gamma and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-gamma. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-gamma and IL-6.

Adolescent↗
PubMed1993

Regulation of Fc-induced IL-6 from human peripheral blood mononuclear cells.

Previous experiments demonstrated that aggregated immunoglobulin and the Fc fragment of human IgG can induce interleukin-6 (IL-6) secretion from peripheral blood monocytes. The data herein indicate that Fc-induced IL-6 is modulated by IL-1, IL-4 and interferon (IFN-gamma). When added with Fc fragments, IL-1 and IFN-gamma increased IL-6 production. IL-4 added with Fc fragment did not influence IL-6 production although IL-4 added with LPS was inhibitory to IL-6 production. However, when PBMC were pre-treated with IL-4, IL-4 downregulated Fc-induced IL-6 secretion. The inhibitory effect of IL-4 in the pre-treatment phase could be overcome with a high concentration of IFN-gamma added with the IL-4. Both IL-4 and IFN-gamma acted in a dose- and time-dependent manner. By dot blot analysis, IL-6 mRNA production appeared to be decreased in amount and duration by IL-4 whereas IFN-gamma increased the amount of IL-6 mRNA production. Hence, IL-4 and IFN-gamma appear to have opposing effects and may play a balancing role in the regulation of IL-6 production secondary to Fc exposure.

Adult↗
PubMed1991

Particle concentration fluorescence immunoassay for measuring interleukin-6 receptor numbers.

Analysis of the number of receptors per cell and the affinity of the ligand/receptor interaction has provided considerable insight into the functioning of numerous cytokines. Interleukin-6 (IL-6) is a multifunctional cytokine which may have considerable clinical relevance in inflammatory or immunodeficiency diseases. Using particle concentration fluorescence immunoassay (PCFIA) technology, an assay is described which calculates the receptor number and affinity on small numbers of human cells. Resting B cells are shown to lack IL-6 receptors but activation of B cells induces up to 1,300 receptors per cell, with Kd of 1 x 10(-11) to 2 x 10(-11) M. Other recombinant mediators do not alter the binding of labeled IL-6 to the cells. PCFIA avoids the use of radioactivity and requires very small numbers of cells (2 x 10(4) per well). Potential application to the study of regulatory mechanisms and to clinical situations where small samples of blood are available is feasible.

Animals↗
PubMed1991

Transplantation of purified islet cells in diabetic rats. III. Immunosuppressive effect of cyclosporin.

This study examined the effect of cyclosporin on the survival of islet beta-cell allografts in streptozocin (STZ)-induced diabetic rats. At a daily oral dose of 5 mg/kg, the agent prevented the rejection of isolated islets, provided they were little contaminated by other pancreatic tissue. The immunosuppressive effect rapidly disappeared after discontinuation of the drug, except when the donor tissue had been pretreated to reduce its nonendocrine content. All recipients of cultured and selected islets maintained a normalized state for greater than 15 wk beyond the 5-wk drug course; this was not the case for shorter periods of treatment. A long-term beneficial effect was also observed in all recipients of purified islet beta-cell grafts, which reversed without treatment in half of the cases. Cyclosporin markedly reduced the mononuclear cell infiltration in each type of islet beta-cell allograft; aggregates of mixed endocrine islet cells were kept virtually infiltration free. Conditions with minimal initial infiltration were associated with long-term graft survival without the need for continuous pharmacological immunosuppression. We conclude that a short-term cyclosporin treatment can induce long-term survival of allografted islet beta-cells, provided the grafts are only slightly contaminated by nonendocrine elements. In rodents, sufficient immunosuppression was achieved by circulating cyclosporin levels of 100-400 ng/ml. Higher concentrations were cytotoxic for cultured islet beta-cells and islet non-beta-cells. A 5-wk treatment with the immunomodulator ciamexone also resulted in long-term survival of purified beta-cell allografts but not of cultured islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗