Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial.

A T-cell receptor (TCR) peptide vaccine from the V beta 5.2 sequence expressed in multiple sclerosis (MS) plaques and on myelin basic protein (MBP)-specific T cells boosted peptide-reactive T cells in patients with progressive MS. Vaccine responders had a reduced MBP response and remained clinically stable without side effects during one year of therapy, whereas nonresponders had an increased MBP response and progressed clinically. Peptide-specific T helper 2 cells directly inhibited MBP-specific T helper 1 cells in vitro through the release of interleukin-10, implicating a bystander suppression mechanism that holds promise for treatment of MS and other autoimmune diseases.

Carcinogenicity and cocarcinogenicity of chromium carbonyl in heterotopic tracheal grafts.

Tracheal grafts, implanted s.c. on syngeneic rats, were used as a bioassay for carcinogenicity or cocarcinogenicity of chromium carbonyl (CC). After a period of revascularization, the lumens of 22 grafts were filled with an agar suspension of 2.5 mg of CC. Twenty-two grafts were filled wit a suspension of 2.5 mg of benzo(a)pyrene (BP) and a mixture of the two chemicals was placed in 24 other grafts. Four controls were exposed to the vehicle only. Eight squamous cell carcinomas developed in the tracheas treated with BP alone and 10 similar neoplasms arose in the CC-BP treated group, but 3 of those induced by CC-BP had metastasized by 9 months. CC alone induced carcinomas in two grafts. The data indicate that this metal carbonyl is a carcinogen that can act synergistically with BP and demonstrate the utility of the technique as an efficient tissue-specific bioassay.

Computer-assisted correlation of structure and biological activity in a set of retinoids.

A computer-assisted pattern-recognition system (ADAPT) designed to elucidate structure-activity relationships was applied to a set of retinoids, potentially useful inhibitors of carcinogenesis. A data set of 67 retinoids was used as input to the ADAPT system; their structures were entered, and their 3-dimensional configurations were optimized by a molecular modelling algorithm. Forty of these retinoids were defined as the "more active" class based upon their ability to reverse keratinization in vitamin A-deficient hamster tracheal organ cultures at 10(-10) M or less. The remaining 27 retinoids were defined as the "less active" class due to their lack of ability to elicit this effect at 10(-8) M or more. Thirteen descriptors were generated by ADAPT for each of these retinoids based upon their structures, including: number of ring atoms; double bonds; del Ré sigma charges; and principal moments. Pattern recognition analysis techniques were applied to this data set to determine if information contained in these descriptors could generate a discriminant function equation which could separate more active from less active retinoids, successfully. Computer recognition of more active from less active retinoids was demonstrated by a number of pattern recognition techniques, and the discriminant function could predict correctly the relative activity of retinoids of "unknown" activity in 87% of trials. These results indicate the existence of distinct structure-activity relationships in this set of biologically important molecules.

Effect of phorbol esters on clonal cultures of human, hamster, and rat respiratory epithelial cells.

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) on the growth of epithelial cells from rat, hamster, and human respiratory tract has been measured by monitoring colony formation and cross-linked envelope formation in culture. TPA and its active derivatives stimulated colony formation of rat tracheal epithelial cells but did not stimulate cross-linked envelope formation. Tracheal epithelial cells from the hamster and human bronchial epithelial cells were inhibited from forming colonies by these agents. This inhibitory effect was also dependent on concentration. In the rat, the stimulation of cells to enter cell division induced by TPA decayed with time after removal of primary cells from the trachea, while in hamster and human cells, the inhibitory effect of TPA was independent of time. Although TPA inhibited colony formation in hamster and human cells, it did not elicit the same responses with respect to cross-linked envelopes. Hamster tracheal epithelial cells did not form cross-linked envelopes in response to TPA, whereas human bronchial cells did. A comparison was made of the response to TPA in cells from the human bronchi of 24 individuals; the extent of inhibition of colony formation induced by TPA varied by 130-fold. These results show that normal cells from these species vary in biological response to tumor promoters, implying that selective induction of terminal differentiation in normal cells may not be a universal mechanism of action of tumor promoters.

Inhibition of transformation of primary rat tracheal epithelial cells by retinoic acid.

The effect of retinoic acid (RA) on N-methyl-N'-nitro-N-nitrosoguanidine-induced transformation of primary cultures of rat tracheal epithelial cells was investigated. RA inhibited transformation of rat tracheal epithelial cells by up to 95% at concentrations of 3.3 to 33 nM which did not substantially affect cell survival. The inhibitory effect of RA on transformation was concentration dependent and was also dependent upon timing and duration of treatment. Treatment with RA for only 1 week following N-methyl-N'-nitro-N-nitrosoguanidine exposure diminished the transformation frequency by 30 to 57%, although longer treatment times were more effective. Because RA was able to inhibit transformation effectively at concentrations which were not substantially inhibitory to colony-forming efficiency of rat tracheal epithelial cells, the mechanism of inhibition of cell transformation does not seem to be related to cytotoxic effects of RA known to occur at high RA concentrations.

Benzo(a)pyrene binding to DNA in organ cultures of human endometrium.

Benzo(a)pyrene was found to bind to DNA in human endometrial tissue in vitro. Among specimens from 41 individuals examined, there was a 70-fold range in the observed specific activities of carcinogen binding to DNA. To determine whether this interindividual variability was correlated with the hormonally determined state of differentiation of the endometrial tissue, this population was subdivided to separate postmenopausal patients from premenopausal patients; among premenopausal patients, further division was made according to location within the menstrual cycle. Tissue obtained late in the proliferative phase or early in the secretory phase of the menstrual cycle had the highest mean specific activity of benzo(a)pyrene binding. In spite of the relatively small group sizes, the observed difference between this and the level of benzo(a)pyrene binding in the mid- and late secretory phases was statistically significant. The average binding level among the small number of patients studied who had entered a natural menopause was lower than the average binding for any of the subgroups of premenopausal patients and significantly lower than the mean for the whole population of premenopausal patients.

High frequency of carcinogen-induced early, preneoplastic changes in rat tracheal epithelial cells in culture.

To study the mechanisms of carcinogenesis, we have developed a system that uses normal cells from an environmentally and epidemiologically relevant tissue, respiratory epithelium. The induction of preneoplastic variants of epithelial cells in culture was quantitated on a per-cell basis following exposure of rat tracheal epithelial (RTE) cells in vitro to the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Following treatment of normal RTE cells, large colonies of altered cells exhibiting an enhanced growth potential under selective culture conditions were observed, while normal RTE cells ceased proliferation after several cell doublings. After further growth in culture, these altered cells acquired the ability to grow in semisolid medium and to produce squamous cell carcinomas when injected into nude mice. The induction of enhanced growth variants of RTE cells by MNNG occurred with a high frequency (greater than or equal to 2.6%/colony-forming cell). In addition, a linear dose-response curve with a slope of approximately 1 was observed when the logarithm of MNNG-induced transformation frequency was plotted versus the logarithm of MNNG dose. These results are consistent with a one-hit mechanism for induction of preneoplastic variants of RTE cells by MNNG. Similar frequencies and kinetics of induction of preneoplastic variants in other culture systems using diploid cells have been observed, suggesting a common mechanism for this early step in carcinogenesis. The RTE cell system will be useful for mechanistic studies of early as well as late changes in the development of neoplasia by epithelial cells.

Metabolism of benzo(a)pyrene in monolayer cultures of human bronchial epithelial cells from a series of donors.

Benzo(a)pyrene [B(a)P] metabolism was measured in monolayer cultures of human bronchial epithelial cells derived from 18 specimens of explanted tissue. Bronchial epithelial cells converted B(a)P to dihydrodiols, phenols, quinone derivatives, and polyhydroxylated forms. Sulfate and glucuronide conjugates of B(a)P metabolites were also detected. Both total metabolism and distribution of metabolites showed a 10-fold or greater variation in cultures from different specimens. When the data were divided according to smoking status, however, no differences in total metabolism, extent of conjugation, or distribution of metabolites could be demonstrated between the two groups. Wide variation (over 1000-fold) in the cytotoxicity of B(a)P towards cells derived from different specimens was demonstrated but could not be directly correlated to the extent of metabolic activation. The results suggest that human bronchial epithelial cells which are newly grown from explanted tissue of smokers in culture do not demonstrate enzymatic induction. Variation among individuals observed in these studies probably represents basal differences in metabolic capability.

Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels.

The induction of DNA adducts and adenomas in the lungs of strain A/J mice has been investigated following the single i.p. administration of each of the following polycyclic aromatic hydrocarbons (PAH): pyrene, dibenz[a,h]anthracene, benzo[a]pyrene, benzo[b]fluoranthene, 5-methylchrysene, and cyclopenta[c,d]pyrene. DNA adducts were measured by 32P-postlabeling at times between 1 and 21 days following injection, while adenomas were counted at 240 days after treatment. Pyrene did not induce either DNA adducts or lung adenomas at any of the doses examined. Each of the remaining PAH induced both adenomas and DNA adducts in a dose-dependent manner, with dibenz[a,h]anthracene > 5-methylchrysene > cyclopenta[c,d]pyrene > benzo[a]pyrene > benzo[b]fluoranthene. DNA adducts reached maximal levels between 3 and 9 days after injection, followed by a gradual decrease. The time-integrated DNA adduct level (TIDAL) was calculated by numerically integrating the areas under the adduct persistence curves extrapolated to 240 days for each PAH at each dose level. This value represents the effective total molecular dose of PAH that was delivered to the lung DNA over the entire course of tumorigenesis. A strong correlation of lung adenoma induction with the TIDAL values was observed for each PAH. The slopes of the tumors versus TIDAL value relationships were essentially identical for 5-methylchrysene, cyclopenta[cd]pyrene, benzo[a]pyrene, and benzo[b]fluoranthene. The slope of this relationship for dibenz[a,h]anthracene was markedly greater. The essentially identical induction of adenomas as a function of TIDAL values for these PAH suggests that the formation and persistence of DNA adducts determines their carcinogenic potency.

Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions.

We determined the TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G --> T transversions at either KRAS (86%) or TP53 (76%), (b) clustered at the G-rich codons 153-158 of TP53 (33%), and (c) had 100% of the guanines of the G --> T transversions on the nontranscribed strand. This mutation spectrum is consistent with an exposure to polycyclic aromatic hydrocarbons, which are the primary component of the smoky coal emissions. These results show that mutations in the TP53 and KRAS genes can reflect a specific environmental exposure.

Human necrotizing vasculitis: immunoglobulins and complement in vessel walls of cutaneous lesions and normal skin.

Immunoglobulins and C3 were detected by immunofluorescence in the blood vessel walls of biopsies of clinically normal skin in patients with active necrotizing vasculitis. Of the 13 patients studied, 9 had C3 and 6 of these had IgM or IgA in biopsies of lesions of vasculitis. In adjacent clinically normal skin, 7 patients had C3 and 3 of these also had IgM or IgA. These findings support the hypothesis that immunoglobulins and complement are present in vessels of some patients prior to chemotaxis of polymorphonuclear leukocytes and the resulting inflammatory purpuric lesions so characteristic of necrotizing vasculitis.

Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis.

BACKGROUND: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an alpha 2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS. OBJECTIVE: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity. SETTING: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada. DESIGN: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg). PATIENTS: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other alpha-noradrenergic agonist, entered the trial. RESULTS: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration. CONCLUSIONS: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS.

OBJECTIVE: To determine whether the MS Functional Composite (MSFC) can predict future disease progression in patients with relapsing remitting MS (RR-MS). BACKGROUND: The MSFC was recommended by the Clinical Outcomes Assessment Task Force of the National MS Society as a new clinical outcome measure for clinical trials. The MSFC, which contains a test of walking speed, arm dexterity, and cognitive function, is expressed as a single score on a continuous scale. It was thought to offer improved reliability and responsiveness compared with traditional clinical MS outcome measures. The predictive value of MSFC scores in RR-MS has not been determined. METHODS: The authors conducted a follow-up study of patients with RR-MS who participated in a phase III study of interferon beta-1a (AVONEX) to determine the predictive value of MSFC scores. MSFC scores were constructed from data obtained during the phase III trial. Patients were evaluated by neurologic and MRI examinations after an average interval of 8.1 years from the start of the clinical trial. The relationships between MSFC scores during the clinical trial and follow-up status were determined. RESULTS: MSFC scores from the phase III clinical trial strongly predicted clinical and MRI status at the follow-up visit. Baseline MSFC scores, and change in MSFC score over 2 years correlated with both disability status and the severity of whole brain atrophy at follow-up. There were also significant correlations between MSFC scores during the clinical trial and patient-reported quality of life at follow-up. The correlation with whole brain atrophy at follow-up was stronger for baseline MSFC than for baseline EDSS. CONCLUSION: MSFC scores in patients with RR-MS predict the level of disability and extent of brain atrophy 6 to 8 years later. MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.

Eight-year follow-up study of brain atrophy in patients with MS.

OBJECTIVE: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. METHODS: A follow-up study was conducted to reassess patients from a phase III trial of interferon beta-1a (IFNbeta-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. RESULTS: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. CONCLUSIONS: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)

BACKGROUND: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. OBJECTIVES: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients. METHODS: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b. RESULTS: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. CONCLUSIONS: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

BACKGROUND AND OBJECTIVE: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. METHODS: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. RESULTS: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment. CONCLUSIONS: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis. Case report and review of literature.

Immunologic evaluation of a patient with pancreatitis, subcutaneous fat necrosis, pleuritis, pericarditis and synovitis is presented. The previously recognized syndrome of pancreatic disease, subcutaneous fat necrosis and arthritis is reviewed. Based on analysis of all the cases described in the English language literature it is suggested that this syndrome be expanded to include polyserositis rather than arthritis alone. Although experimental and clinical evidence tends to implicate physiocochemical tissue injury by pancreatic lipase as the primary pathogenic mechanism in this syndrome, studies in our patient suggest the possible contribution of immune-mediated injury. Supporting data include eosinophilia, biopsy demonstration of vasculitis antedating the subcutaneous fat necrosis, immunofluorescent identification of immunoglobulin G (IgG) and C3 in the pleura, and reduced levels of total hemolytic complement in the serum, and pleural and pericardial effusions.

Clinical and physiologic studies of two siblings with prekallikrein (Fletcher factor) deficiency.

Two siblings with hereditary Fletcher factor (prekallikrein) deficiency were studied for alterations of fibrinolysis, platelet function, skin inflammatory responses, permeability factor (PF/dil) formation and leukocyte chemotaxis. In vivo stimulation of fibrinolytic activity was normal; the bleeding time and platelet functions (adhesivity, aggregation, release reaction) were also normal. Both immediate (wheal-flare reaction to histamine, bradykinin, prostaglandin E1, physical agents) and delayed sensitivity skin test reactions were within normal limits. Migration of subjects' leukocytes to attractants in skin windows and in Boyden-type chambers was the same as that of control leukocytes. Serum complement components were essentially normal. One subject's leukocytes showed normal tissue factor production on stimulation by endotoxin, although prekallikrein deficiency did impair the endotoxin-stimulated generation of serum procoagulant activity. PF/dil caused increased vessel permeability in human skin; in vitro generation of PF/dil required both the Hageman factor and prekallikrein. The Fletcher factor-deficient subjects responded in a normal manner to PF/dil. Based on the Fletcher factor-coagulation assay, the biologic half-disappearance time of prekallikrein (after the transfusion of normal plasma in one of the subjects) was estimated at 35 hours. Therefore, these studies suggest that severe prekallikrein (Fletcher factor) deficiency in man is not associated with any clinically significant impairment in hemostasis, fibrinolysis, inflammatory responses or leukocyte function.

Myelin basic protein-specific T lymphocytes induce chronic relapsing experimental autoimmune encephalomyelitis in lymphocyte-deficient (SCID) mice.

Myelin basic protein (BP)-specific T lymphocyte cell lines were selected from the lymph nodes (LN) of BP-immunized, H-2d, CXJ-1 mice prior to the onset of clinical disease. These CD4+ T cells induced severe acute experimental autoimmune encephalomyelitis (EAE) in MHC-compatible (H-2d), lymphocyte-deficient (SCID) mice (C.B-17scid/scid). The incidence of disease was much higher in immunodeficient SCID mice (71%) than in syngeneic immunocompetent CXJ-1 mice (5%). SCID mice with EAE had an acute progressive paralytic disease with inflammation and myelin loss detected in the spinal cord. Eighty-six percent (12/14) of mice followed for more than 2 weeks had 1 or more relapses of EAE. These results demonstrate that clinical remission and relapse of EAE can be induced by the single adoptive transfer of a LN-derived BP-specific T cell line in the absence of host-derived effector and regulatory lymphocytes. Furthermore, the data demonstrate that the pathogenic potential of BP-specific T cells is greater in lymphocyte-deficient SCID mice compared with immunocompetent mice, suggesting that autoreactive T cells are controlled by potent inhibitory mechanisms associated with regulatory lymphocytes. These results are relevant to mechanisms of disease remission and relapse mediated by lymphocytes involved in paralytic inflammatory diseases such as multiple sclerosis (MS).

Encephalitogenic T lymphocytes develop from SJL/J hematopoietic cells transplanted into severe combined immunodeficient (SCID) mice.

Previously, we constructed chimeras by injecting hematopoietic cells from experimental autoimmune encephalomyelitis (EAE)-susceptible SJL (H-2s) strain mice into severe combined immunodeficient (SCID) C.B-17scid/scid (H-2d) mice. These SCID mouse-SJL mouse hematopoietic cell chimeras developed passive EAE following adoptive transfer of PLP S139-151-specific SJL T lymphocyte line cells, but were resistant to active EAE induced by primary immunization with PLP S139-151. In order to gain an understanding of the encephalitogenic potential of transplanted hematopoietic progenitors in SCID mouse-SJL mouse chimeras, we attempted to induce EAE in hematopoietic chimeras constructed with or without an additional SJL fetal thymus implant. Chimeras with the thymus implant were susceptible to passive and active EAE while chimeras without the thymus implant were susceptible to passive but not active EAE. Encephalitogenic, CD4+, TCR+ T lymphocytes were selected in vitro from PLP S139-151-immunized, thymus-implanted chimeras. These results showed that hematopoietic SJL progenitors developed into antigen-presenting accessory cells and immunocompetent encephalitogenic T lymphocytes following transplantation into SCID mice. The development of primary immune reactivity depended on a fetal thymus implant for expression in SCID mouse-SJL mouse chimeras.