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PubMed2003

Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance.

Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.

Analgesics, Opioid↗
PubMed1987

The relationship of addiction, tolerance, and dependence to alcohol and drugs: a neurochemical approach.

Alcohol and drug addiction are defined in behavioral terms as the preoccupation with, compulsive use of, and relapse to drugs that are descriptive and confirmatory. The basis of addiction may involve neurochemical changes in the brain that distort and redirect the drive states (instincts). Tolerance and dependence may only be incidentally associated with addiction as a result of a nonspecific adaptation by the body to the presence of a drug. The cellular adaptation may be the same in all organs. Addiction to alcohol and drugs may have no specific relationship to tolerance and dependence. Addiction occurs in the absence of observable tolerance and dependence to alcohol and drugs. Alcohol and drug addiction is probably more complex than tolerance and dependence. Addiction is difficult to study because of the variability of behavioral phenomena and the underlying intricacies of the neurosubstrates. Tolerance and dependence are still useful as they are indicators of drug use. It is a misconception that long term chronic use is necessary for tolerance and dependence to develop. Some studies have shown that tolerance can develop within hours and days to a single dose of alcohol or other drugs. Anxiety, depression and insomnia can occur after a single dose of ethanol in humans. These symptoms of withdrawal from the alcohol or drug constitute dependence. Redefining the criteria for addiction tolerance and dependence to alcohol and other drugs may be in order. A neurochemical model may provide a more definitive and uniform basis for considering addiction, tolerance, and dependence to alcohol and drugs.

Brain Chemistry↗
PubMedDate not supplied

Acute alcohol tolerance in cognitive and psychomotor performance: influence of the alcohol dose and prior alcohol experience.

Using tests for cognitive performance (the Pauli test) and psychomotor coordination (the Pursuit Rotor test), the interaction between the drinking history of the subjects, the alcohol dose, and acute alcohol tolerance were examined in light and moderate alcohol consumers (N = 10). Both groups of subjects were tested with doses of alcohol corresponding to 0.5 and 1.0 g/kg. Dose order was random and tests were carried out at an interval of 1 week. Reports of the subjects' previous experience with alcohol indicated that the moderate consumers ingested alcohol in higher quantities than the light consumers. The light consumers were rather inexperienced with frequent alcohol consumption at the quantities investigated, as were the moderate consumers for the higher of the alcohol doses used. Acute tolerance was assessed by comparing performance at equal concentrations of alcohol on the ascending and the descending limbs of the alcohol concentration curve. In the test for cognitive performance, both doses of alcohol in light alcohol consumers yielded significant differences between the ascending and descending limbs of the alcohol concentration curve, suggesting the existence of acute tolerance. In the moderate alcohol consumers, only a tendency to acute tolerance was observed for the higher of the doses tested. In the test for the psychomotor performance, both of the measures of frequency (of misses) and duration (of time outside the target area) were used. The results showed that in the light consumers, acute tolerance was seen for both of the doses, and to some extent for both of the dependent measures (frequency and duration) investigated. However, in the moderate alcohol consumers, acute tolerance was only observed for the higher of the doses and only for the duration measure. Given the difference in drinking history between the two groups of subjects, the implication would be that when the dose of alcohol exceeds the subjects' prior experience, acute tolerance seems inevitable. The present results clearly demonstrate the complexity of the acute tolerance phenomenon, and emphasize the fact that the results are dependent on the subjects' prior experience with alcohol as well as the dose of alcohol ingested, and consequently suggest the interaction between acute and chronic alcohol tolerance.

Adult↗
PubMed2004

Detection of regulatory cells as an assay for allograft tolerance in miniature swine.

BACKGROUND: There is currently a great need for an in vitro assay to assess the presence of tolerance following allotransplantation to determine whether immunosuppressive medications can be discontinued. Our laboratory has recently developed an assay involving coculture inhibition of cell-mediated lympholysis that correlates with tolerance to allografts in swine leukocyte antigen (SLA) Class I-mismatched miniature swine. The potential for clinical application of this assay may depend on 2 important factors: (1) whether the assay can be used in the presence of immunosuppression; and (2) whether frozen-stored naive responder cells can be utilized. METHODS: Long-term tolerant MGH miniature swine that had accepted SLA Class I-mismatched kidney transplants after a 12-day course of cyclosporine or tacrolimus were studied. Two long-term tolerant and 2 naive control animals were treated with a clinically relevant dose of cyclosporine for 2 weeks (trough level 100 to 400 ng/ml) to simulate the ongoing "chronic" immunosuppression used in human recipients of allografts. Cells from tolerant or naive, recipient-matched animals were stimulated for 6 days with donor or third-party SLA. These primed cells were then cocultured with naive unstimulated recipient major histocompatibility complex (MHC)-matched responders and irradiated stimulators. Responder cells were tested both fresh and frozen. RESULTS: Suppression of cytotoxic responses of naive responder cells was observed in all coculture assays using cells from tolerant animals primed against donor antigen in vitro, but not in assays using similarly primed cells from naive animals. Responder cells from tolerant animals receiving immunosuppression had a suppressive activity similar to that from cells of the same animals not receiving immunosuppression. Similar suppression was also observed in coculture assays using either fresh or frozen naive responder cells. CONCLUSIONS: This coculture assay appears to correlate with the presence of tolerance under conditions applicable to the clinical setting. The assay appears to identify peripheral regulatory mechanisms of tolerance in allogeneic transplant recipients, and therefore may provide an approach for determining an appropriate timepoint at which to test withdrawal of immunosuppressive medications.

Animals↗
PubMed2004

D-penicillamine-induced autoimmunity in the Brown Norway rat: role for both T and non-T splenocytes in adoptive transfer of tolerance.

The D-penicillamine autoimmune syndrome observed in Brown Norway (BN) rats is similar to an idiosyncratic reaction seen in some patients. We have previously shown that 2 weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally observed in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. We demonstrated that this tolerance is immune-mediated; tolerance to D-penicillamine is long lasting, we can adoptively transfer splenocytes from tolerant rats into slightly irradiated naive syngeneic recipients, and rats exposed to low dose D-penicillamine produce tolerogenic cytokines [Masson, M. J., and Uetrecht, J. P. (2004) Tolerance induced by low dose D-penicillamine in the brown norway rat model of drug-induced autoimmunity is immune-mediated. Chem. Res. Toxicol. 17, 82-94]. The aim of this study was to provide further understanding of the cells that are responsible for transferring tolerance and to assess the presence of regulatory T cells in the spleen of tolerant animals. We cotransferred T cells or splenocytes depleted of T cells from tolerant BN rats with splenocytes from naive BN rats into lightly irradiated syngeneic recipients. We found that neither tolerant splenocyte subpopulation could completely prevent clinical signs of autoimmunity. These results demonstrate that immune tolerance to D-penicillamine-induced autoimmunity may require both antigen presenting cells and T cells.

Administration, Oral↗
PubMed2004

Genetic analysis of rapid tolerance to ethanol's incoordinating effects in mice: inbred strains and artificial selection.

Ethanol tolerance, a decrease in drug responsiveness with repeated administrations, is an important diagnostic criterion for alcoholism. Rapid tolerance develops within 8-24 hours of an initial ethanol exposure and shares many similarities with chronic tolerance. The genetic contribution to rapid tolerance to ethanol-induced ataxia was estimated using a panel of inbred strains of mice. Strains differed significantly in the degree of rapid tolerance development, which had a broad-sense heritability estimate of 0.11. Artificial selection was carried out to develop lines of mice that would show High (HRT) and Low (LRT) levels of Rapid Tolerance. Starting with HS/Npt mice, derived from a systematic cross of eight inbred strains, a significant response to selection was seen in replicate 1 by the third selection generation. No difference was found in replicate 2. Heritability estimates after the fourth generation were 0.25 for HRT-1 mice and 0.06 for LRT-1 mice. HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol. These studies provide evidence for a genetic contribution to rapid tolerance and support a genetic link between rapid and chronic tolerance to ethanol's ataxic effects.

Animals↗
PubMed1987

Associative control of tolerance to the sedative effects of a short-acting benzodiazepine.

The role of Pavlovian conditioning in tolerance to the depressant effect of a benzodiazepine (midazolam) on the ambulatory activity of rats was examined. The depression of activity by low doses (1.0 and 4.0 mg/kg, ip) of midazolam diminished quickly over repeated doses given at 48-hr intervals (Experiment 1). Equivalent tolerance was observed in groups measured at 2 min and 30 min after drug injection. When challenged with saline, however, drug-tolerant animals tested immediately after injection were hyperactive in comparison with nontolerant controls, whereas equivalent groups tested 30 min after injection were not. A second context was designed, and its discriminability from the original was established by assessing context-specific suppression of activity following exposure to mild electric shock (Experiment 2). In Experiment 3A, although tolerant animals tested in the drug-associated context remained fully tolerant, a second group demonstrated a complete loss of tolerance when given the drug in a saline-associated context. Both groups were fully tolerant when tested again in the drug-associated context after 14 drug-free days. In Experiment 3B, tolerance was significantly reduced by 14 extinction exposures to the drug-associated environment without the drug. These results are uniquely predicted by associative models of drug tolerance and may have implications for the clinical use of this class of drugs.

Animals↗
PubMed2006

Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms.

Analgesics↗
PubMed1998

Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand-producing antigen presenting cells.

A major problem associated with adenovirus gene therapy is the T cell-mediated immune response, which is elicited by inoculation of the adenovirus vector and leads to rapid clearance of the virus and loss of transgene expression. In this study, the immune response to adenovirus was prevented by induction of specific T-cell tolerance by pretreatment with adenovirus-infected antigen-presenting cells (APC) that express Fas ligand. Compared with control-treated mice, the tolerized mice showed prolonged expression of lacZ upon administration of AdCMVlacZ 1 week after tolerance induction. In contrast to the control mice, the tolerized mice did not display proliferation of CD3+ T cells in the spleen in response to AdCMVlacZ. Tolerance induction also was indicated by the lower production of interferon-gamma and interleukin-2 by peripheral T cells isolated from AdCMVlacZ-challenged tolerized mice than by AdCMVlacZ-challenged control-treated mice. The T-cell tolerance was specific for the adenovirus as the T-cell responses to irrelative murine cytomegalovirus remained unimpaired. Our results indicate that adenovirus-specific T-cell tolerance can be induced by APCs that coexpress Fas ligand and adenovirus antigens. We propose that this new strategy can be used to induce tolerance to adenovirus vector gene therapy with resultant prolonged expression of the transgene.

Adenoviridae↗
PubMed2001

Modest lifestyle intervention and glucose tolerance in obese African Americans.

OBJECTIVE: Previous studies have demonstrated the benefit of short-term diets on glucose tolerance in obese individuals. The purpose of this study was to evaluate the effectiveness of modest lifestyle changes in maintaining improvements in glucose tolerance induced by short-term energy restriction in obese African Americans with impaired glucose tolerance or type 2 diabetes mellitus. RESEARCH METHODS AND PROCEDURES: An intervention group (n = 45; 47 +/- 1 year [mean +/- SE]), 105 +/- 4 kg; body mass index: 39 +/- 1 kg/m(2)) received an energy-restricted diet (943 +/- 26 kcal/d) for 1 week, followed by a lifestyle program of reduced dietary fat (-125 kcal/d) and increased physical activity (+125 kcal/d) for 1 year. Body weight and plasma concentrations of glucose, insulin, and C-peptide during an oral glucose tolerance test were measured at baseline, 1-week, and 4-month intervals. A control group (n = 24; 48 +/- 1 year; 110 +/- 5 kg; body mass index: 41 +/- 2 kg/m(2)) underwent these measurements at 4-month intervals. RESULTS: No changes in weight or glucose tolerance were observed in the control group. The intervention group had significant (p < 0.05) improvements in body weight and glucose tolerance in response to the 1-week diet, which persisted for 4 months (p < 0.001 vs. control for change in weight). A total of 19 subjects (42%) continued the intervention program for 1 year, with sustained improvements (weight: -4.6 +/- 1.0 kg; p < 0.001 vs. control; oral glucose tolerance test glucose area: -103 +/- 44 mM. min; p < 0.05 vs. control). DISCUSSION: A modest lifestyle program facilitates weight loss and enables improvements in glucose tolerance to be maintained in obese individuals with abnormal glucose tolerance. However, attrition was high, despite the mild nature of the program.

Adult↗
PubMed1996

Different expression of IL-2 receptor alpha-chain on a lamina propria T cell population and goblet cells in rats orally tolerized or sensitized to ovalbumin (OA) after colonization with an OA-producing Escherichia coli.

The aim of this study was to compare the local gut immune response in sensitized and orally tolerized experimental animals. The development of IgE/IgG antibodies and the DTH to OA was studied in rats made orally tolerant to OA and compared with sensitized control rats after colonization with an Escherichia coli genetically engineered to produce OA. At 3 weeks of age, pups were weaned onto a standard diet without OA or an OA-containing diet for 4 weeks and then switched to a standard diet without OA. Both groups of rats were parenterally immunized with a mixture of OA and human serum albumin (HSA) in Freund's complete adjuvant when they were 8 weeks old. After DTH measurement 2 weeks later, all rats were colonized with an E. coli producing OA for 5 days. The local immune response in the small intestine was assessed, using immunohistochemistry, as the expression of MHC class II molecules and IL-2 receptor (IL-2R) alpha-chain. The OA-tolerant rats showed the classical signs of oral tolerance, with a reduced IgE and IgG antibody and DTH response to OA before colonization. The difference between the two groups in the anti-OA antibody response became even more pronounced after colonization with the E. coli that produce OA. Rats orally tolerant to OA maintained a normal villus architecture after colonization, with a normal expression of MHC class II molecules similar to non-treated adult rats, but with a significantly higher (P = 0.004) expression of IL-2R alpha-chain on T cells in the lamina propria of the villus core compared with sensitized control rats. The tolerant rats showed a very weak staining with the anti-IL-2R alpha-chain-specific antibody on a few goblet cells in only one out of seven rats. In the sensitized control rats, a marked local immune response was seen with an intense staining with a monoclonal anti-IL-2R alpha-chain-specific antibody on goblet cells in five out of seven rats (P = 0.019) and also an increased expression of MHC class II molecules in the epithelial cells and cells in the lamina propria of all rats. Rats orally tolerant to OA maintained a normal villus architecture after colonization, but with a significantly higher (P = 0.004) expression of IL-2R alpha-chain on T cells in the lamina propria of the villus core compared with sensitized control rats. The novel finding that goblet cells express IL-2R alpha-chain and the striking difference in expression of the receptor and the numbers of goblet cells between tolerant and sensitized rats may suggest a direct T cell regulation of the goblet cells. A possibility that oral tolerance might be maintained by the activated T cells expressing IL-2R alpha-chain in the lamina propria of the villus core is also discussed.

Administration, Oral↗
PubMed2000

T-cell tolerance induction is normal in the (NZB x NZW)F1 murine model of systemic lupus erythematosus.

The (New Zealand black (NZB) x New Zealand white (NZW))F1 (NZB/W) mouse strain spontaneously develops an autoimmune disease characterized by anti-dsDNA antibody production and glomerulonephritis. Although evidence suggests that production of pathogenic autoantibodies is T-cell dependent, the immunological defects that lead to activation of these autoreactive T cells are unknown. In particular, it has not been resolved whether autoreactive T cells become activated in these mice because of a generalized defect in T-cell tolerance induction. Previous work has demonstrated that thymic and peripheral tolerance to strongly deleting antigens are intact in NZB/W mice. In this study we investigate whether these mice possess a more subtle T-cell tolerance defect. To this end, we have produced NZB/W mice carrying a transgene encoding beef insulin (BI) which is expressed at levels close to the threshold for T-cell tolerance induction. In BALB/c mice this transgene produces a profound but incomplete state of BI-specific T-cell tolerance, mediated predominantly by clonal anergy. Comparison of BI-specific tolerance in NZB/W, major histocompatibility complex (MHC)-matched (BALB/c x NZW)F1, and BALB/c BI-transgenic mice clearly demonstrates that T-cell tolerance induction is normal in NZB/W mice. The data suggest that the loss of T-cell tolerance that ultimately supports nephritogenic autoantibody production in NZB/W mice does not result from a generalized defect in T-cell tolerance, and by extension likely results from aberrant activation of specific autoreactive T cells.

Animals↗
PubMed2002

T-cell activation occurs simultaneously in local and peripheral lymphoid tissue following oral administration of a range of doses of immunogenic or tolerogenic antigen although tolerized T cells display a defect in cell division.

How the mucosal immune system promotes active immunity against harmful organisms but tolerance to commensal bacteria or dietary antigens is poorly understood. Thus, the antigen-presenting cell (APC), site of antigen presentation, and effector mechanisms responsible for oral priming and tolerance remain unclear. Characterizing differences between oral priming and tolerance may improve the exploitation of oral tolerance for therapeutic applications and aid the design of oral vaccines. To address these questions we compared the mucosal and systemic activation and localization of antigen-specific T cells during the induction of oral priming and tolerance. Activation marker expression and cell division by tg T cells was determined in conjunction with their anatomical location. These studies show that after feeding, T cells are activated in both peripheral and local lymphoid tissues within 6 hr, irrespective of the presence of adjuvant. Subsequently, T-cell accumulation can be detected simultaneously in peripheral and mesenteric lymph nodes and Peyer's patches within 24 hr of feeding, but only after 3 days post feeding in the lamina propria. Primed and tolerized T cells adopted similar phenotypes as assessed by activation marker expression. However, within the mesenteric lymph nodes (MLN) tolerized T cells underwent significantly fewer divisions than primed T cells. Thus, T-cell activation and expansion occurs throughout the animal after feeding a range of doses of antigen, irrespective of whether priming or tolerance is the eventual outcome. However, the presence of an adjuvant enhances clonal expansion in the MLN while tolerized T cells display defective cell division.

Administration, Oral↗
PubMed2003

The balance of deletion and regulation in allograft tolerance.

Although the precise mechanisms involved in the establishment and maintenance of peripheral allograft tolerance are still not fully understood, it is now clear that acquisition of transplantation tolerance is an active, highly regulated, multistep process. According to the pool size model of allograft tolerance, the allograft outcome, rejection, or tolerance, often depends on the balance between cytopathic and regulatory T cells (Tregs). Although both deletion and regulation play important roles in allograft tolerance, our recent studies showed that the quantitative details for each mechanism differ from model to model. Therefore, we hypothesize that there is a delicate balance between deletion and regulation in allograft tolerance. In a model of allograft tolerance in which the deletional mechanism plays a dominant role, e.g. tolerance produced via creation of mixed chimeras, the regulatory mechanism, albeit sometimes present, is far less important. Whilst in a model in which the regulation mechanism plays a critical role, e.g. donor-specific transfusion plus MR1-induced allograft tolerance, a deletional mechanism lowers the threshold for effective Treg action.

Animals↗
PubMed2006

[Allergic contact dermatitis: how to re-induce tolerance?].

Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the development of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-beta. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively.

Allergens↗
PubMed2001

Induction of stable long-term mixed hematopoietic chimerism following nonmyeloablative conditioning with T cell-depleting antibodies, cyclophosphamide, and thymic irradiation leads to donor-specific in vitro and in vivo tolerance.

BACKGROUND: Successful transplantation of solid organs relies on long-term immunosuppression for the prevention of graft rejection. Donor-specific tolerance without the need for continuous immunosuppression can be observed after allogeneic BMT. However, its routine use for tolerance induction has been precluded so far by the high conditioning-related toxicity of standard BMT regimens. Our laboratory has recently established a cyclophosphamide (CTX) plus thymic irradiation (TI)-based nonmyeloablative conditioning protocol for the treatment of hematologic malignancies. We have recently described the successful clinical application of this approach for the induction of donor-specific tolerance in a patient receiving a living-related kidney transplant, which resulted in graft acceptance without long-term immunosuppression. The aim of this study was to evaluate the induction and maintenance of host-versus-graft tolerance following this CTX-plus-TI-based regimen in a mouse model. METHODS: Induction of mixed hematopoietic chimerism and development of donor-specific tolerance following the CTX-based nonmyeloablative conditioning regimen (200 mg/kg CTX, in vivo T-cell depletion [anti-CD4 monoclonal antibody (MoAb) GK1.5 and anti-CD8 MoAb 2.43], and 7 Gy TI) was studied in the fully major histocompatibility complex (MHC)-mismatched B10.A (H2a)-->B6 (H2b) strain combination. RESULTS: The conditioning regimen allowed allogeneic bone marrow engraftment and persistent (>30 weeks) mixed lymphohematopoietic chimerism in almost all recipients. TI was essential to allow engraftment and development of tolerance, which was evident in all lasting chimeras. Compared to animals receiving a similar TBI-based conditioning regimen, overall levels of chimerism were significantly lower in the CTX-plus-TI-conditioned animals. However, donor-specific tolerance in vitro and in vivo was evident in CTX-plus-TI-conditioned chimeras. Tolerance was associated with the presence of donor-type MHC class II+ cells in the thymus and deletion of donor-reactive cells, as determined by Mtv-8 and Mtv-9 superantigen-mediated deletion of Vbeta11+ and Vbeta5/1.2+ T cells. CONCLUSION: Engraftment, long-term chimerism, and induction of donor-specific tolerance can be achieved using a nonmyeloablative CTX-based conditioning regimen in fully MHC-mismatched BMT recipients without the induction of GVHD.

Animals↗
PubMed2000

Abnormal glucose tolerance, not small vessel diameter, is a determinant of long-term prognosis in patients treated with balloon coronary angioplasty.

AIMS: We sought to find out what factors are important for long-term prognosis, the small vessel itself or abnormal glucose tolerance, in patients treated with coronary angioplasty. BACKGROUND: Patients with coronary artery disease with diabetes mellitus often show diffuse and small coronary artery narrowing. Impaired glucose tolerance has also been reported to be a risk factor for cardiovascular disease. METHODS: Among 584 patients who underwent first elective balloon coronary angioplasty, diabetes mellitus and impaired glucose tolerance were present in 197 patients. Large and small vessels were defined by reference vessel diameter before coronary angioplasty as either larger or smaller than 2.5 mm. Patients were categorized into the following four groups: 175 patients with normal glucose tolerance and reference diameter <2.5 mm (group SN), 212 patients with normal glucose tolerance and reference diameter greater than or = 2.5 mm (group LN), 101 patients with abnormal glucose tolerance and reference diameter <2.5 mm (group SD), and 96 patients with abnormal glucose tolerance and reference diameter greater than or = 2.5 mm (Group LD). The cardiac events were compared for a period of 8 years after coronary angioplasty among the four groups. RESULTS: There was no difference in the percentage diameter stenosis immediately after coronary angioplasty among the four groups. However, group SD showed unfavourable prognosis despite similar minimal lumen diameter after coronary angioplasty compared with group SN. Event-free survival curve of group LD showed a sudden drop approximately 5 years after the coronary angioplasty. In multivariate analysis, the cardiac events were associated with the presence or absence of abnormal glucose tolerance. Furthermore, patients with bad glycaemic control (HbA1c>6.0%) at index coronary angioplasty showed worse event free survival than those with good glycaemic control. CONCLUSIONS: An important determinant for long-term prognosis after coronary angioplasty is a presence of abnormal glucose tolerance per se and not small vessel diameter.

Adult↗
PubMed2002

[Influence of impaired glucose tolerance on long-term survival after acute myocardial infarction].

BACKGROUND AND OBJECTIVE: An impaired glucose tolerance as well as type 2 diabetes are associated with an increased cardiovascular mortality. This study was undertaken to determine whether this is also true for impaired glucose tolerance in immediate temporal relation with an acute myocardial infarction (AMI). PATIENTS AND METHODS: The survival of 562 patients (232 females, 330 males; age 68 +/- 13 years) consecutively admitted to the intensive care unit of a medical department with the diagnosis of AMI, were prospectively evaluated over a span of more than 3 years. Type 2 diabetes had been previously known in 152, while it was newly diagnosed in 83 patients. Oral glucose tolerance tests (OGTT) were performed in 129, but the test was not performed in 222 patients. Survival was analysed with the Kaplan-Meier test. RESULTS: Among the 129 patients who had had an OGTT, it was normal in 60 (47%), 45 (35%) had impaired glucose tolerance and 24 (19%) were found to have previously undiagnosed diabetes (WHO criteria). Survival of all patients with type 2-diabetes was significantly worse than in the remainder of patients (p < 0.0001). In patients with impaired glucose tolerance the survival time was significantly shorter than in those with normal glucose tolerance (p = 0.029). Even after excluding those patients who had died in the acute post-infarction phase, the difference between patients with normal and with impaired glucose tolerance remained significant (p = 0.034). CONCLUSION: Patients with impaired glucose tolerance have a significantly shorter survival after AMI than those with a normal glucose tolerance. Blood glucose concentration 2 hours after oral glucose intake thus seems to be an important predictor of death after AMI.

Aged↗