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PubMed2005

Subcellular localization of copper in tolerant and non-tolerant plant.

The ability of Elsholtzia splendens Naki (E. splendens) to accumulate copper appears to be governed by its high degree of coppertolerance. However, the tolerance mechanism on the physiological basis is unknown. Using transmission electron microscope (TEM) and energy dispersive analysis of X-rays (EDX), the likely location of copper within the cells of the tolerant and non-tolerant was determined. Here the role of vacuolar and cell wall compartmentalization in this copper tolerant plant were investigated. A direct comparison of copper locations of E. splendens and the non-tolerant Astragalus sinicus L. (A. sinicus) showed that the majority of copper in the tolerant was localized primarily in the vacuolar, cell wall, on the plasmamembrane, beside lipid grains induced by copper pollution, in the chloroplasts and amyloids; but in the non-tolerant, copper precipitates only be observed on the plasmamembrane, in the chloroplasts and cytoplasm under copper exposure conditions that were toxic to both species. This revealed that the tolerant accumulates more copper in the vacuole and cell wall than the non-tolerant, where was regarded as the storage compartment of tolerant plant or hyperaccumulator for heavy metals.

Adaptation, Physiological↗
PubMed1976

Persisting T cells in rats tolerant of human serum albumin. The significance of tolerant and nonimmune T cells which preferentially restrict high affinity antibody synthesis.

The adoptive response of primed rat thoracic duct lymphocytes ('TDL) following specific antigen challenge (soluble human serum albumin, s-HSA) was restricted when cells were transferred into syngeneic, adult (AS2 X AS)F1 hybrid recipients in comparison with irradiated hosts. This adoptive memory response was also inhibited in irradiated recipients by transferring nonimmune TDL along with 'TDL. Recirculating B cells (B-TDL) did not inhibit the 'TDL response, indicating that the adoptive secondary response was regulated by T cells. Antibody synthesis was preferentially restricted in the high affinity memory cell precursor population, demonstrating a role for T cells in regulating the maturation of antibody affinity. The adoptive memory response was liberated from this T regulatory effect in adult recipients when hosts were challenged with the alum-precipitated adjuvant form (HSA-adj) rather than the soluble form of HSA. Since the adoptive memory response was sensitive to the presence or absence of T cells, this experimental model was used to determine whether or not T cells were eliminated from HSA-tolerant rats. Antibody synthesis by 'TDL was reduced approximately 10-fold compared with controls when transferred into tolerant recipients and challenged with either s-HSA or HSA-adj; a similar reduction was not observed by substituting bovine serum albumin (BSA) 'TDL and challenging with s-BSA. The tolerance-induced inhibition of HSA 'TDL was destroyed by irradiation and TDL from HSA-tolerant donors were more effective than normal nonimmune TDL in reducing the adoptive HSA 'TDL response. HSA-tolerant TDL did not inhibit the BSA 'TDL response significantly. The results indicate that T cells are not eliminated by tolerance induction in this model and after interaction with tolerogen may exert an active (or competitive) role in restricting antibody synthesis by high affinity B memory cell precursors. However, the fact that tolerant T cells are not able to prevent a primary response suggests that unresponsiveness to HSA in the T compartment represents a functional deficiency and not an active suppression at this level. Nevertheless, the presence of these tolerant cells probably accounts for the failure of antibody affinity to mature in partially tolerant rats.

Animals↗
PubMed2000

Tolerance to the anticonvulsant effects of lamotrigine on amygdala kindled seizures: cross-tolerance to carbamazepine but not valproate or diazepam.

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.

Amygdala↗
PubMed1992

Acute and chronic ethanol tolerance: operant behaviour in naive and ethanol tolerant rats.

The relationship between tolerance to ethanol and acute tolerance to ethanol was examined. One group of rats was given 1.8 g/kg ethanol, and another group was administered 18 ml/kg saline for 26 days after sessions. Animals responded under a fixed ratio ten (FR-10) schedule of food reinforcement. Thereafter, various doses of ethanol (1.3-2.5 g/kg) were examined to assess the influence of the ethanol treatment on the expression of acute tolerance. Acute tolerance was assessed by comparing the performance at equal concentrations of ethanol on the ascending and the descending limbs of the ethanol concentration curve. This was achieved by varying the time between behavioural tests since ethanol administration. Ethanol concentrations were estimated using a rebreathed air procedure. Equal concentrations of ethanol were achieved with doses of i) 1.3 g/kg (10 min post-injection, PI), and 1.8 g/kg (60 min PI), as well as with doses of ii) 2.0 g/kg (10 min PI), and 2.5 g/kg (60 min PI). Acute tolerance was demonstrated for the initially ethanol naive animals. For the animals given ethanol chronically, only doses of ethanol higher than the chronically administered dose produced evidence for acute tolerance. When the chronically dosed animals had been off ethanol for 67 days, there was evidence for acute tolerance. The present data add to the generality of the acute ethanol tolerance phenomenon, and emphasize both the appearance as well as the loss of tolerance for this effect.

Animals↗
PubMed2005

Requirement of a higher degree of chimerism for skin allograft tolerance in cyclophosphamide-induced tolerance.

By using a cyclophosphamide (CP)-induced tolerance system, we previously raised the possibility that the degree of chimerism might determine the induction of heart and skin allograft tolerance. When C3H (H-2k; Thy1.2, Mls-1b) mice were intravenously primed with 1 x 10(8) spleen cells (SCs) from H-2 matched AKR (H-2k; Thy1.1, Mls-1a) mice and then treated intraperitoneally with 200 mg/kg CP, the survival of AKR skin grafts was permanently prolonged in a tolerogen-specific fashion. After this treatment, a minimal degree of mixed chimerism and the clonal destruction of Mls-1a-reactive CD4+Vbeta6+ T cells in the periphery were observed. When AKR SCs and 100 mg/kg CP were used for conditioning, the survival of the AKR skin grafts was mildly prolonged. The clonal destruction of CD4+Vbeta6+ T cells in the periphery was induced and a minimal degree of mixed chimerism was detectable. The degree of mixed chimerism induced with AKR SCs and 200 mg/kg CP was significantly higher than that with AKR SCs and 100 mg/kg CP during the observation. On the other hand, neither skin allograft prolongation nor permanent mixed chimerism could be induced when C3H mice were treated with AKR SCs and 50 mg/kg CP. In order to increase the degree of mixed chimerism, we injected 1 x 10(8) tolerant AKR SCs on day 3 into the recipient C3H mice that had been treated with AKR SCs on day 0 and with 100 mg/kg CP on day 2. The reason that we used tolerant SCs was that untreated AKR SCs caused graft-versus-host disease in most of the recipients. Tolerant AKR SCs were harvested from AKR mice that had been treated with C3H SCs and 200 mg/kg CP 2 weeks earlier, and did not contain regulatory cells. By adoptive transfer, the degree of chimerism was stably and significantly increased in all recipients, and AKR skin graft tolerance was induced in half of the recipients. T-cell-depleted bone marrow cells (BMCs) from untreated AKR mice induced skin allograft tolerance in 83% of recipients. Thus, the present study strongly confirmed the hypothesis that a higher degree of chimerism is required for the induction of skin allograft tolerance in CP-induced tolerance.

Adoptive Transfer↗
PubMed2005

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats.

RATIONALE: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations. OBJECTIVES: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops. METHODS: During an initial 3-h administration of 60% nitrous oxide (N(2)O), male Long-Evans rats were screened for N(2)O's hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N(2)O or placebo gas. Core temperature was measured telemetrically. RESULTS: Rats that exhibited a comparable degree of hypothermia during an initial N(2)O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N(2)O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N(2)O exposure, the II group breathing N(2)O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N(2)O exposures. CONCLUSIONS: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent-adaptive responses may mediate this relationship.

Animals↗
PubMed1992

Differential inhibition by NMDA antagonists of rapid tolerance to, and cross-tolerance between, ethanol and chlordiazepoxide.

We have recently found that the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present report we show that they also block rapid cross-tolerance from chlordiazepoxide to ethanol as well as ethanol to chlordiazepoxide. However, NMDA antagonists fail to block the development of rapid tolerance to chlordiazepoxide. Our results suggest that NMDA antagonists may affect not only the acquisition of rapid tolerance or cross-tolerance to sedatives but also the ability to express that tolerance or cross-tolerance, depending on the drugs used. It is also possible that the phenomena of rapid tolerance and rapid cross-tolerance have basic differences not previously reported in the literature.

Animals↗
PubMed1985

Tolerance to morphine-induced analgesia in mice: magnetic fields function as environmental specific cues and reduce tolerance development.

Mice receiving daily injection of morphine (10 mg/kg) developed tolerance to morphine-induced analgesia, such that after 5-7 days of treatment their thermal response (paw licking) latencies in the hot plate test were indistinguishable from those of control animals. Exposure to a rotating magnetic field for thirty minutes before the daily morphine administrations significantly reduced the development of tolerance. These magnetic exposures also significantly increased over 7-10 days the basal nociceptive thresholds and paw licking response latencies of saline treated mice. Control and sham exposed mice that were fully tolerant to the analgesic effects of morphine failed to show any tolerance to morphine-induced analgesia when exposed to the magnetic stimuli prior to injection. Likewise, the partial tolerance to morphine shown by mice exposed to the rotating magnetic field pre-injection environmental cues was eliminated when control or sham pre-injection cues lacking the magnetic stimuli were provided. In all cases tolerance to morphine-induced analgesia was evident in the subsequent re-test with the original cues. These results indicate that magnetic field exposure can reduce the development of tolerance to the analgesic effects of morphine. They also show that magnetic stimuli function as significant environmental cues for the development of tolerance to morphine-induced analgesia. This suggests that magnetic stimuli affect both the associative (classical conditioning) and non-associative (physiological, pharmacological) mechanisms involved in the development of opiate tolerance.

Analgesia↗
PubMed1990

Reverse tolerance to amphetamine evokes reverse tolerance to 5-hydroxytryptophan.

Repeated intermittent administration of amphetamine in mice caused reverse tolerance to 5-hydroxy-L-tryptophan (5-HTP)-induced head twitch, as well as to amphetamine-induced stereotypy. The repeated administration of 5-HTP alone also resulted in reverse tolerance in the head-twitch test. Daily pretreatment with haloperidol prior to amphetamine administration blocked the development of both reverse tolerance to amphetamine and to 5-HTP, whereas daily pretreatment with cyproheptadine prior to amphetamine blocked only the reverse tolerance to 5-HTP. On the other hand, 5-HTP-induced reverse tolerance was blocked by daily pretreatment with cyproheptadine, but not with haloperidol. There appears to be no difference in the persistence of the reverse tolerance to 5-HTP, whether induced by amphetamine or by 5-HTP; in both instances, the persistence does not correlate with the persistence of reverse tolerance to amphetamine. The data suggest that the reverse tolerance to amphetamine and the associated reverse tolerance to 5-HTP are independent events, both of which are mediated by dopaminergic mechanisms.

5-Hydroxytryptophan↗
PubMedDate not supplied

Effects of initial tolerance on acquired tolerance to alcohol in two selectively bred rat strains.

The extent to which initial sensitivity to alcohol influences acquired tolerance was investigated in two selectively bred rat lines. These two lines have been selectively bred for differences in initial sensitivity to alcohol. The most affected (MA) line shows about a 90% reduction in motor activity following a 1.5 g/kg dose of alcohol compared with only a 40% reduction in least affected (LA) animals. In an initial investigation using stabilimeter activity, MA animals demonstrated increased tolerance following regular alcohol exposure, while LA animals showed little change from their initial levels of tolerance. In a second study following a similar intubation procedure, tolerance was assessed by sleeping time. Both MA and LA rats evidenced increased tolerance to alcohol, although MA animals did not approach the levels of tolerance shown by LA animals. In both studies the amount of initial tolerance was correlated with the degree of acquired tolerance. The potential for using these animals in the study of the underlying mechanisms of tolerance is discussed.

Animals↗
PubMedDate not supplied

Genotype regulates the development of tolerance to ethanol and cross-tolerance to nicotine.

The long-sleep (LS) and short-sleep (SS) mouse lines were selectively bred for differential sensitivity to the anesthetic actions of ethanol, but they also differ in sensitivity to nicotine. A recent study suggested that the LS mice develop more tolerance to ethanol and cross-tolerance to nicotine than do the SS following chronic ethanol treatment. The studies reported here expand on these previous studies by assessing potential tolerance to ethanol and cross-tolerance to nicotine using additional behavioral and physiological measures. In addition, the effects of chronic ethanol treatment on ethanol and nicotine metabolism were measured. The LS mice developed tolerance to ethanol as measured by effects on open-field activity, body temperature, and sleep time, whereas the SS mice did not develop consistent tolerance to ethanol's effects on any of these measures. Cross-tolerance to nicotine's effects on open-field activity and body temperature developed, but only in the LS mice. The ethanol tolerance is likely due to changes in CNS sensitivity to ethanol, but altered elimination of nicotine may explain much of the cross-tolerance to nicotine seen in chronic ethanol-treated LS mice.

Absorption↗
PubMed1995

Tolerance to naloxone-induced suppression of intake: learning and cross-tolerance to cholecystokinin in rats.

Experiments were conducted to evaluate the contribution of conditioning to tolerance to the meal-suppressive effect of naloxone (Nx) in rats. The results indicated (a) Nx suppresses consumption in a dose-dependent manner; (b) tolerance to this suppression of intake is "contingent" (the rat must eat in conjunction with drug administration for tolerance to develop); (c) tolerance is displayed only in the context of environmental cues previously associated with Nx; (d) Nx-tolerant rats overeat when presented with cues previously associated with the drug; (e) Nx-tolerant rats display cross-tolerance to cholecystokinin. The results are consistent with C.X. Poulos and H. Cappell's (1991) "homeostatic" theory of tolerance, as well as with the results of other experiments indicating that conditioning contributes to tolerance to many effects of various drugs.

Animals↗
PubMed2001

Genetics of larval urea and ammonia tolerance and cross-tolerance in Drosophila melanogaster.

Five laboratory populations of Drosophila melanogaster previously selected for over 60 generations for larval resistance to ammonium chloride (NH4Cl), and five populations selected for over 60 generations for larval resistance to urea, were investigated to determine the genetic mechanisms through which such tolerance had evolved. To examine the genetics of tolerance to urea and ammonia, egg-to-adult survivorship and developmental time were measured at two different NH4Cl levels and two different urea levels for each selection regime relative to the control lines, and among reciprocal crosses between each selection regime and the control lines. To examine tolerance to novel nitrogenous compounds (cross-tolerance), egg-to-adult survivorship and developmental time were measured at two different NH4Cl levels and two different urea levels for reciprocal crosses between the selection lines. Dominance is a major genetic factor in egg-to-adult survivorship in the presence of either urea or ammonia, while cross-tolerance to novel nitrogenous compounds also shows dominance as a major genetic mechanism controlling egg-to-adult survivorship. Dominance and X-linkage appear to be factors affecting developmental time in the presence of either urea or ammonia, although we could not exclude cytoplasmic inheritance as influencing our results. Cross-tolerance to novel nitrogenous compounds shows dominance and X-linkage as the main genetic factors controlling developmental time. We develop a simple hypothesis, in accordance with the results, that there may be two X-linked loci: one controlling urea tolerance and one controlling ammonia tolerance, and one autosomal locus exerting a pleiotropic control of tolerance. However, many other possibilities exist.

Ammonium Chloride↗
PubMed1990

Differential response to benzylpenicillin in vivo of tolerant and non-tolerant variants of Streptococcus sanguis II.

A variant that was highly tolerant to benzylpenicillin was obtained from a non-tolerant clinical isolate of Streptococcus sanguis II by repeated exposure to penicillin. The rabbit model of endocarditis was used to investigate the efficacy of a high dose regimen of benzylpenicillin (250 mg/kg; peak serum concentration c. 25 mg/l) in the prophylaxis and treatment of endocarditis during challenge or infection with the non-tolerant parent strain or its tolerant variant. The two strains exhibited a similar capacity to initiate infection. A single dose of penicillin administered 0.5 h before bacterial challenge protected six of nine rabbits infected with the non-tolerant parent strain, but none of nine infected with the tolerant variant. Treatment of established infection with penicillin administered twice daily for four days cured eight of 13 (61%) rabbits infected with the non-tolerant parent strain, but only one of 14 (7%) rabbits infected with the tolerant variant. These results support the view that tolerance to penicillin has therapeutic implications.

Drug Tolerance↗
PubMed1995

Demonstration of cells possessing tolerance-inducing activity in Xenopus laevis rendered tolerant perimetamorphically.

J-strain (JJ) Xenopus laevis is easily made tolerant to semixenogeneic (X laevis x X borealis: JB) adult skin grafted onto immunologically competent larvae at stages 53-54. If the larvae are thymectomized shortly before skin grafting (late Txd), tolerance will never be induced. This suggests that suppression of the immune response to JB skin is mediated by a population of thymus-derived cells. In an attempt to confirm the presence of these cells, the spleen and tolerated JB skin were tested for their tolerance-inducing activity, by grafting either spleen or skin and a new JB skin piece simultaneously to late Txd JJ larva (secondary host). The results clearly indicated that both spleen and skin possessed the ability to induce tolerance. The injection of 1 x 10(5) splenocytes resulted in induction of tolerance in more than 80% of secondary hosts, and the rate of tolerance induction increased in relation to the injected cell number. Furthermore, tolerance was induced in about 90% of the animals by injecting as few as 100 cells isolated from the tolerated skin. Immunohistochemical observation of grafted skin showed that many host-derived T cells were distributed around the epidermal basal lamina. These results indicate that the cells with suppressive activity are a population of T cells that have differentiated in metamorphosing thymuses and have been released peripherally.

Animals↗
PubMed1996

Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not contribute to maintenance of tolerance.

A nonmyeloablative conditioning regimen has recently been developed that allows allogeneic marrow engraftment with induction of permanent mixed chimerism and donor-specific tolerance across fully MHC-mismatched allogeneic barriers. We recently demonstrated that tolerance can be broken in these chimeras by administration of an anti-donor class I-specific monoclonal antibody that eliminates donor hematopoietic cells. We have now investigated the role of the thymus in the loss of tolerance observed when chimerism is eliminated in this manner. Mixed chimeras were prepared in B10 (H2b) recipients by treatment with depleting anti-CD4 and anti-CD8 mAbs, 3-Gy whole body irradiation, and 7-Gy thymic irradiation, followed by B10.A (H2a) bone marrow transplantation. Chimeras were thymectomized 7 weeks later, and were either untreated or were depleted of donor cells with anti-donor class I (Dd-specific) mAb 34-2-12. Control chimeras that were not thymectomized also received anti-donor monoclonal antibodies or no further treatment. Of the four groups, only euthymic animals that were depleted of donor antigen showed a loss of tolerance, as evidenced by rejection of B10.A skin grafts. In contrast to untreated control and thymectomized, anti-Dd-treated chimeras, these euthymic anti-Dd-treated chimeras showed significant recovery of Vbeta11+ T cells, which can recognize Mtv antigens presented by donor I-E molecules. The requirement for a thymus for loss of tolerance in the absence of donor antigen was verified in an adoptive transfer model, in which chimera (B10.A-->B10) spleen cells were depleted of donor-type cells ex vivo, adoptively transferred into B6 nu/nu mice, and then further depleted of donor-type antigen with monoclonal antibody treatment in vivo. These B6 nu/nu mice maintained donor-specific tolerance to B10.A skin grafts. The absence of active suppression as a potent mechanism of tolerance in long-term mixed chimeras was confirmed by the loss of mixed chimerism and of tolerance that was readily induced by injection of naive host-type spleen cells. Together, our results suggest that in mixed allogeneic chimeras, intrathymic clonal deletion, and not peripheral suppression or anergy, is the major mechanism maintaining donor-specific tolerance.

Animals↗
PubMed2001

Induction of transplantation tolerance with a short course of tacrolimus (FK506): I. Rapid and stable tolerance to two-haplotype fully mhc-mismatched kidney allografts in miniature swine.

BACKGROUND: Inbred miniature swine provide a large animal model in which the effects of selective major histocompatibility complex (MHC) matching can be reproducibly studied. We have previously demonstrated that although a 12-day course of cyclosporine uniformly induces tolerance to class I-mismatched renal allografts, it does not induce tolerance across full MHC barriers. In this study, we assessed whether and at what dose tacrolimus might permit allografts to induce tolerance across different MHC barriers. METHODS: Recipients of MHC disparate renal allografts were treated with a 12-day course of tacrolimus by continuous intravenous infusion. Groups were divided as follows: (1) class I-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=3); (2) fully MHC-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=2); and (3) fully MHC-mismatched kidneys with 0.12-0.16 mg/kg/day tacrolimus (n=4). RESULTS: In groups 1 and 2, recipients with tacrolimus levels of 45-80 ng/ml accepted renal allografts long-term with stable renal function. Donor-specific hyporesponsiveness was demonstrated by cell-mediated lymphocytotoxicity and mixed lymphocyte response, and subsequent donor-matched grafts were also accepted, without further immunosuppression (n=4), confirming systemic tolerance. In group 3, recipients that achieved tacrolimus levels of 35 ng/ml (n=2) accepted their grafts without chronic changes, whereas recipients with levels of 20-26 ng/ml (n=2) developed chronic allograft glomerulopathy, suggesting 35 ng/ml as the threshold blood level for tolerance induction. In vitro assays demonstrated that peripheral blood lymphocytes from tolerant animals produced inhibitory cytokines, suggesting the involvement of regulatory mechanisms. CONCLUSIONS: To our knowledge, this study represents the first demonstration of the induction of transplant tolerance across a two-haplotype full MHC barrier with a short course of immunosuppression in a large animal model. These studies may also have clinical applicability, because the time course required to induce tolerance was sufficiently short that the high drug levels required might be expected to be tolerated clinically with only transient toxicity.

Animals↗
PubMed1998

How do monoclonal antibodies induce tolerance? A role for infectious tolerance?

One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mild-1980s that CD4 antibodies can induce immunological tolerance without depleting CD4+ T cells has reawakened interest in the use of nondepleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of facilitating tolerance. In order to apply to principle of reprogramming in the clinic, we have sought to understand the mechanisms that are involved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (+/- CD8) antibodies can be shown to block the rejection process while selectively promoting the development of CD4+ regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never been exposed to CD4 antibodies become tolerant to grafted antigens by experiencing antigen in the microenvironment of regulatory T cells. Dominant tolerance is not the only mechanism that can be facilitated by CD4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion. The mechanism by which regulatory CD4+ T cell suppress is not yet defined but could be active or passive. We have proposed the "civil service model" to explain how tolerant T cells might interfere with the responses of competent T cells in such a way as to render them tolerant.

Animals↗