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Biomedical subjects

K A Campbell

Publications and source records attributed to K A Campbell.

At least 19 recordsLinked to original sources

The pigmented "black" neuroendocrine tumor of the pancreas: a question of origin.

BACKGROUND: Pigmented neoplasms are extremely rare in the pancreas, and, when black pigment is identified, it often suggests the diagnosis of metastatic melanoma. The authors describe two patients with pigmented "black" neuroendocrine tumors of the pancreas. One patient had an incidental (0.5 cm) finding, and the second patient had a well-demarcated, 4.5-cm mass identified by computerized tomography that was consistent with an islet cell tumor. METHODS: The two neoplasms were resected surgically and studied by light microscopy using hematoxylin and eosin (H&E), Fontana-Masson, and iron stains. The neoplasms were examined immunohistochemically, and ultrastructural analysis was performed. RESULTS: H&E stains revealed nests of well-differentiated cells with small, round, centrally placed nuclei. The cytoplasm of the neoplastic cells was pink and granular and contained abundant brown-black pigment. Angiolymphatic and perineural invasion were identified in the larger neoplasm. Both neoplasms demonstrated a positive reaction with a Fontana-Masson stain, which was susceptible to bleaching, and a negative reaction to an iron stain. Immunohistochemical stains showed that neoplastic cells expressed chromogranin and synaptophysin but did not express HMB-45, S-100 protein, glucagon, or insulin. Ultrastructural examination revealed regular neurosecretory granules (100-150 nm) and large, irregularly shaped, electron-dense granules with small lipid inclusions consistent with lipofuscin. CONCLUSIONS: These pigmented pancreatic neoplasms are similar histologically and radiographically to the "black adenoma" of the adrenal gland. It is important to recognize these tumors, because they may mimic metastatic melanoma.

Aged↗

Dual-mode EPR study of Mn(III) salen and the Mn(III) salen-catalyzed epoxidation of cis-beta-methylstyrene.

Dual-mode electron paramagnetic resonance (EPR), in which an oscillating magnetic field is alternately applied parallel or perpendicular to the static magnetic field, is a valuable technique for studying both half-integer and integer electron spin systems and is particularly useful for studying transition metals involved in redox chemistry. We have applied this technique to the characterization of the Mn(III) salen (salen = N,N'-ethylene bis(salicylideneaminato)) complex [(R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III)], with an S = 2 integer electron spin system. Furthermore, we have used dual-mode EPR to study the Mn salen complex during the Mn(III) salen-catalyzed epoxidation of cis-beta-methylstyrene. Our study shows that the additives N-methylmorpholine N-oxide (NMO) and 4-phenylpyridine-N-oxide (4-PPNO), which are used to improve epoxidation yields and enantioselection, bind to the Mn(III) center prior to the epoxidation reaction, as evidenced by the alteration of the Mn(III) parallel mode EPR signal. With these additives as ligands, the axial zero-field splitting values and (55)Mn hyperfine splitting of the parallel mode signal are indicative of an axially elongated octahedral geometry about the Mn(III) center. Since the dual-mode EPR technique allows the observation of both integer and half-integer electron spin systems, Mn oxidation states of II, III, IV, and potentially V can be observed in the same sample as well as any radical intermediates or Mn(III,IV) dinuclear clusters formed during the Mn(III) salen-catalyzed epoxidation reaction. Indeed, our study revealed the formation of a Mn(III,IV) dinuclear cluster in direct correlation with expoxide formation. In addition to showing the possible reaction intermediates, dual-mode EPR offers insight into the mechanism of catalyst degradation and formation of unwanted byproducts. The dual-mode technique may therefore prove valuable for elucidating the mechanism of Mn(III) salen catalyzed reactions and ultimately for designing optimum catalytic conditions (solvents, oxidants, and additives such as NMO or 4-PPNO).

Journal Article↗

Does histidine 332 of the D1 polypeptide ligate the manganese cluster in photosystem II? An electron spin echo envelope modulation study.

The tetranuclear manganese cluster in photosystem II is ligated by one or more histidine residues, as shown by an electron spin echo envelope modulation (ESEEM) study conducted with [(15)N]histidine-labeled photosystem II particles isolated from the cyanobacterium Synechocystis sp. strain PCC 6803 [Tang, X.-S., Diner, B. A., Larsen, B. S., Gilchrist, M. L., Jr., Lorigan, G. A., and Britt, R. D. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 704-708]. One of these residues may be His332 of the D1 polypeptide. Photosystem II particles isolated from the Synechocystis mutant D1-H332E exhibit an altered S(2) state multiline EPR signal that has more hyperfine lines and narrower splittings than the corresponding signal in wild-type PSII particles [Debus, R. J., Campbell, K. A., Peloquin, J. M., Pham, D. P., and Britt, R. D. (2000) Biochemistry 39, 470-478]. These D1-H332E PSII particles are also unable to advance beyond an altered S(2)Y(Z)(*) state, and the quantum yield for forming the S(2) state is very low, corresponding to an 8000-fold slowing of the rate of Mn oxidation by Y(Z)(*). These observations are consistent with His332 being close to the Mn cluster and modulating the redox properties of both the Mn cluster and tyrosine Y(Z). To determine if D1-His332 ligates the Mn cluster, we have conducted an ESEEM study of D1-H332E PSII particles. The histidyl nitrogen modulation observed near 5 MHz in ESEEM spectra of the S(2) state multiline EPR signal of wild-type PSII particles is substantially diminished in D1-H332E PSII particles. This result is consistent with ligation of the Mn cluster by D1-His332. However, alternate explanations are possible. These are presented and discussed.

Cyanobacteria↗

Thoracolumbar immobilization for trauma patients with torso gunshot wounds: is it necessary?

BACKGROUND: Previous studies have suggested that patients transported by emergency medical services (EMS) following major trauma had a longer injury-to-treatment interval and a higher mortality rate than their non-EMS-transported counterparts. HYPOTHESIS: There is little actual benefit of thoracolumbar immobilization for patients with torso gunshot wounds (GSW). DESIGN: Retrospective analysis of prospectively gathered data from the Maryland Institute for Emergency Medical Service Systems State Trauma Registry from July 1, 1995, through June 30, 1998. SETTINGS: All designated trauma centers in Maryland. PATIENTS: All patients with torso GSW. MAIN OUTCOME MEASURES: (1) A patient was considered to have benefited from immobilization if he or she had less than complete neurologic deficits in the presence of an unstable vertebral column, as shown by the need for operative stabilization of the vertebral column; (2) mortality. RESULTS: There were 1000 patients with torso GSW. Among them, 141 patients (14.1%) had vertebral column and/or spinal cord injuries. Two patients (0.2%) (95% confidence interval, -0.077% to 0.48%) required operative vertebral column stabilization, while 6 others required other spinal operations for decompression and/or foreign body removal. The presence of vertebral column injury was actually associated with lower mortality (7.1% vs 14.8%, P<.02). CONCLUSIONS: This study suggests that thoracolumbar immobilization is almost never beneficial in patients with torso GSW, and that a higher mortality rate existed among those GSW patients without vertebral column injury vs those with such injuries. The role of formal thoracolumbar immobilization for patients with torso GSW should be reexamined.

Adult↗

Neurobehavioral deficits in Persian Gulf veterans: additional evidence from a population-based study.

Reports of low-concentration nerve gas exposures during the Gulf War (GW) have spurred concern about possible health consequences and symptoms reported by many returning veterans. The Portland Environmental Hazards Research Center is studying veterans from the northwest United States who report persistent, unexplained "Gulf War" symptoms (cases) and those who do not report those symptoms (controls). An epidemiological survey focused on exposures and symptoms was mailed to a random sample of GW veterans from Oregon and southwestern Washington. Volunteers recruited from survey respondents agreed to undergo a thorough medical examination and psychological and neurobehavioral assessment. Persistent symptoms with no medical explanation associated with Persian Gulf service (e.g., fatigue, muscle pain, memory deficits) beginning during or after the war qualified respondents as cases. The 239 cases with unexplained symptoms and the 112 controls without symptoms were administered a computerized assessment battery of 12 psychosocial and 6 neurobehavioral tests. Replicating and extending previous interim findings, a subgroup of veterans emerged from the initial analysis in the form of extreme outliers which produced a visually and quantitatively obvious bimodal distribution. This led, as it had previously, to analyses of the outliers as a separate group (labeled "slow ODTP"), which confirmed the initial findings of neurobehavioral differences between the outliers and the other cases and controls and provided more convincing evidence that the majority of cases who report neurobehavioral symptoms have no objective evidence of neurobehavioral deficits. However, the larger group of symptomatic veterans do have highly significant and compelling evidence of psychological distress based on scores from 11 separate psychological tests. Whereas the cases differed from the controls by poorer neurobehavioral test performance, extraction of the slow ODTP participants (almost all cases) eliminated neurobehavioral performance differences between the remaining cases and the controls and provided support for the hypothesis that the slow ODTP cases might have been from the unhealthy end of the GW population prior to the war. However, there was no evidence of poor motivation, pre-GW educational differences, or greater association with abnormal psychological function in this group than in other cases or controls.

Adult↗

The Kentucky Homeplace Project: family health care advisers in underserved rural communities.

The Kentucky Homeplace Project (KHP) is a state-legislated program designed to address well-documented deficits in the health status of and health resources available to many of Kentucky's rural residents. Since its inception in 1994, the KHP has served approximately 80,000 clients, primarily through home visits by trained, locally residing paraprofessionals known as family health care advisers. These family health care advisers employ culturally appropriate strategies to meet immediate needs as well as to foster long-term client empowerment and the adoption of health prevention strategies. This descriptive examination of KHP provides information regarding (a) the advantages of the program, with specific attention to its orientation toward provision of culturally appropriate health services; (b) the disadvantages of KHP, including competing budgetary priorities and its vulnerability to local economic and political trends; and (c) the potential application of similar programs for other rural, difficult-to-reach populations.

Family Health↗

Social stress induces glucocorticoid resistance in macrophages.

Stress-induced levels of plasma glucocorticoid hormones are known to modulate leukocyte function. These experiments examined the effects of a social stressor on the responsiveness of peripheral immune cells. Male mice experienced six evening cycles of social disruption (SDR), in which an aggressive male intruder was placed into their home cage for 2 h. Although circulating corticosterone was elevated in SDR mice, they had enlarged spleens and increased numbers of splenic leukocytes. Splenocytes from SDR and control mice were cultured with lipopolysaccharide and corticosterone. Cells from SDR mice exhibited decreased sensitivity to the antiproliferative effects of corticosterone, suggesting that the peripheral immune cells were resistant to glucocorticoids. In addition, SDR cells produced more interleukin (IL)-6. To determine which cell population was affected, we used antibody-labeled magnetic beads to deplete splenocyte suspensions of B cells or macrophages. Depletion of macrophages from SDR cultures, but not depletion of B cells, abolished both the corticosterone resistance and enhanced IL-6 secretion. These findings demonstrate that a psychosocial stressor induced glucocorticoid resistance in mouse splenic macrophages.

Aggression↗

Use of buccal cells collected in mouthwash as a source of DNA for clinical testing.

CONTEXT: To maximize the participation rate in population genetic studies, alternatives to invasive whole blood collection are increasing. One such alternative is buccal epithelial cell collection, which, in contrast to venipuncture and finger sticks, is painless. Buccal cells, if collected and purified efficiently, offer an acceptable source for DNA to be used in research and clinical applications. OBJECTIVE: To develop a noninvasive sampling method for collecting cells for routine DNA testing in a clinical laboratory setting. DESIGN: Five factors were used to evaluate several brands of mouthwash: (1) compatibility with the DNA purification chemistry, (2) DNA yield, (3) DNA quality, (4) DNA stability at room temperature, and (5) mouthwash taste. Next, an optimization study was undertaken to maximize DNA yield. Finally, a validation study was undertaken with the optimized protocol to test a panel of 14 donors for DNA yield and performance and to test for the stability of DNA held in mouthwash. SETTING: Industrial research and development laboratory. RESULTS: Of 5 mouthwashes tested, Scope brand mouthwash received the highest overall ranking. The addition of proteinase K and glycogen to the protocol significantly enhanced DNA yields, with a test panel (n = 14) giving a range of 12 to 60 microg of DNA per donor. In a 4-week room temperature stability study, the DNA in mouthwash samples was found to be stable for at least 2 weeks. CONCLUSION: A clinically validated DNA purification chemistry was adapted to a noninvasive specimen collection method. This method used a commercially available mouthwash, Scope, to collect buccal epithelial cells for the preparation of high-quality DNA in high yield.

Cheek↗

Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses.

Gulf War unexplained illnesses (GWUI) are a heterogeneous collection of symptoms of unknown origin known to be more common among veterans of the Gulf War than among nonveterans. In the present study we focused on one of these unexplained illnesses. We tested the hypothesis that in a sample of Persian Gulf War veterans chronic fatigue syndrome (CFS) was associated with cognitive deficits on computerized cognitive testing after controlling for the effects of premorbid cognitive differences. We obtained Armed Forces Qualification Test (AFQT) data acquired around the date of induction into the military on 94 veterans of the Gulf War, 32 with CFS and 62 healthy controls. Controls performed better than participants diagnosed with CFS on the AFQT. Cognitive deficits were associated with CFS on 3 of 8 variables after the effect of premorbid AFQT scores was removed with ANCOVA.

Adult↗

Glutamate 189 of the D1 polypeptide modulates the magnetic and redox properties of the manganese cluster and tyrosine Y(Z) in photosystem II.

Recent models for water oxidation in photosystem II postulate that the tyrosine Y(Z) radical, Y(Z)(*), abstracts both an electron and a proton from the Mn cluster during one or more steps in the catalytic cycle. This coupling of proton- and electron-transfer events is postulated to provide the necessary driving force for oxidizing the Mn cluster in its higher oxidation states. The formation of Y(Z)(*) requires the deprotonation of Y(Z) by His190 of the D1 polypeptide. For Y(Z)(*) to abstract both an electron and a proton from the Mn cluster, the proton abstracted from Y(Z) must be transferred rapidly from D1-His190 to the lumenal surface via one or more proton-transfer pathways. The proton acceptor for D1-His190 has been proposed to be either Glu189 of the D1 polypeptide or a group positioned by this residue. To further define the role of D1-Glu189, 17 D1-Glu189 mutations were constructed in the cyanobacterium Synechocystis sp. PCC 6803. Several of these mutants are of particular interest because they appear to assemble Mn clusters in 70-80% of reaction centers in vivo, but evolve no O(2). The EPR and electron-transfer properties of PSII particles isolated from the D1-E189Q, D1-E189L, D1-E189D, D1-E189N, D1-E189H, D1-E189G, and D1-E189S mutants were examined. Intact PSII particles isolated from mutants that evolved no O(2) also exhibited no S(1) or S(2) state multiline EPR signals and were unable to advance beyond an altered Y(Z)(*)S(2) state, as shown by the accumulation of narrow "split" EPR signals under multiple turnover conditions. In the D1-E189G and D1-E189S mutants, the quantum yield for oxidizing the S(1) state Mn cluster was very low, corresponding to a > or =1400-fold slowing of the rate of Mn oxidation by Y(Z)(*). In Mn-depleted D1-Glu189 mutant PSII particles, charge recombination between Q(A)(*)(-) and Y(Z)(*) in the mutants was accelerated, showing that the mutations alter the redox properties of Y(Z) in addition to those of the Mn cluster. These results are consistent with D1-Glu189 participating in a network of hydrogen bonds that modulates the properties of both Y(Z) and the Mn cluster and are consistent with proposals that D1-Glu189 positions a group that accepts a proton from D1-His190.

Amino Acid Substitution↗

Histidine 332 of the D1 polypeptide modulates the magnetic and redox properties of the manganese cluster and tyrosine Y(Z) in photosystem II.

An electron spin-echo envelope modulation study [Tang, X.-S., Diner, B. A., Larsen, B. S., Gilchrist, M. L., Jr., Lorigan, G. A., and Britt, R. D. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 704-708] and a recent Fourier transform infrared study [Noguchi, T., Inoue, Y., and Tang, X.-S. (1999) Biochemistry 38, 10187-10195], both conducted with [(15)N]histidine-labeled photosystem II particles, show that at least one histidine residue coordinates the O(2)-evolving Mn cluster in photosystem II. Evidence obtained from site-directed mutagenesis studies suggests that one of these residues may be His332 of the D1 polypeptide. The mutation D1-H332E is of particular interest because cells of the cyanobacterium Synechocystis sp. PCC 6803 that contain this mutation evolve no O(2) but appear to assemble Mn clusters in nearly all photosystem II reaction centers [Chu, H.-A., Nguyen, A. P. , and Debus, R. J. (1995) Biochemistry 34, 5859-5882]. Photosystem II particles isolated from the Synechocystis D1-H332E mutant are characterized in this study. Intact D1-H332E photosystem II particles exhibit an altered S(2) state multiline EPR signal that has more hyperfine lines and narrower splittings than the S(2) state multiline EPR signal observed in wild-type PSII particles. However, the quantum yield for oxidizing the S(1) state Mn cluster is very low, corresponding to an 8000-fold slowing of the rate of Mn oxidation by Y(Z)(*), and the temperature threshold for forming the S(2) state is approximately 100 K higher than in wild-type PSII preparations. Furthermore, the D1-H332E PSII particles are unable to advance beyond the Y(Z)(*)S(2) state, as shown by the accumulation of a narrow "split" EPR signal under multiple turnover conditions. In Mn-depleted photosystem II particles, charge recombination between Q(A)(*)(-) and Y(Z)(*) in D1-H332E is accelerated in comparison to wild-type, showing that the mutation alters the redox properties of Y(Z) in addition to those of the Mn cluster. These results are consistent with D1-His332 being located near the Mn-Y(Z) complex and perhaps ligating Mn.

Cyanobacteria↗

Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial.

OBJECTIVE: To evaluate the endpoints of complications (specifically pancreatic fistula and total complications) and death in patients undergoing pancreaticoduodenectomy. SUMMARY BACKGROUND DATA: Four randomized, placebo-controlled, multicenter trials from Europe have evaluated prophylactic octreotide (the long-acting synthetic analog of native somatostatin) in patients undergoing pancreatic resection. Each trial reported significant decreases in overall complication rates, and two of the four reported significantly lowered rates of pancreatic fistula in patients receiving prophylactic octreotide. However, none of these four trials studied only pancreaticoduodenal resections, and all trials had high pancreatic fistula rates (>19%) in the placebo group. A fifth randomized trial from the United States evaluated the use of prophylactic octreotide in patients undergoing pancreaticoduodenectomy and found no benefit to the use of octreotide. Prophylactic use of octreotide adds more than $75 to the daily hospital charge in the United States. In calendar year 1996, 288 patients received octreotide on the surgical service at the authors' institution, for total billed charges of $74,652. METHODS: Between February 1998 and February 2000, 383 patients were recruited into this study on the basis of preoperative anticipation of pancreaticoduodenal resection. Patients who gave consent were randomized to saline control versus octreotide 250 microg subcutaneously every 8 hours for 7 days, to start 1 to 2 hours before surgery. The primary postoperative endpoints were pancreatic fistula, total complications, death, and length of hospital stay. RESULTS: Two hundred eleven patients underwent pancreaticoduodenectomy with pancreatic-enteric anastomosis, received appropriate saline/octreotide doses, and were available for endpoint analysis. The two groups were comparable with respect to demographics (54% male, median age 66 years), type of pancreaticoduodenal resection (60% pylorus-preserving), type of pancreatic-enteric anastomosis (87% end-to-side pancreaticojejunostomy), and pathologic diagnosis. The pancreatic fistula rates were 9% in the control group and 11% in the octreotide group. The overall complication rates were 34% in the control group and 40% in the octreotide group; the in-hospital death rates were 0% versus 1%, respectively. The median postoperative length of hospital stay was 9 days in both groups. CONCLUSIONS: These data demonstrate that the prophylactic use of perioperative octreotide does not reduce the incidence of pancreatic fistula or total complications after pancreaticoduodenectomy. Prophylactic octreotide use in this setting should be eliminated, at a considerable cost savings.

Aged↗

Postoperative bile duct strictures: management and outcome in the 1990s.

OBJECTIVE: To describe the management and outcome after surgical reconstruction of 156 patients with postoperative bile duct strictures managed in the 1990s. SUMMARY BACKGROUND DATA: The management of postoperative bile duct strictures and major bile duct injuries remains a challenge for even the most skilled biliary tract surgeon. The 1990s saw a dramatic increase in the incidence of bile duct strictures and injuries from the introduction and widespread use of laparoscopic cholecystectomy. Although the management of these injuries and short-term outcome have been reported, long-term follow-up is limited. METHODS: Data were collected prospectively on 156 patients treated at the Johns Hopkins Hospital with major bile duct injuries or postoperative bile duct strictures between January 1990 and December 1999. With the exception of bile duct injuries discovered and repaired during surgery, all patients underwent preoperative percutaneous transhepatic cholangiography and placement of transhepatic biliary catheters before surgical repair. Follow-up was conducted by medical record review or telephone interview during January 2000. RESULTS: Of the 156 patients undergoing surgical reconstruction, 142 had completed treatment with a mean follow-up of 57.5 months. Two patients died of reasons unrelated to biliary tract disease before the completion of treatment. Twelve patients (7.9%) had not completed treatment and still had biliary stents in place at the time of this report. Of patients who had completed treatment, 90. 8% were considered to have a successful outcome without the need for follow-up invasive, diagnos tic, or therapeutic interventional procedures. Patients with reconstruction after injury or stricture after laparoscopic cholecystectomy had a better overall outcome than patients whose postoperative stricture developed after other types of surgery. Presenting symptoms, number of stents, interval to referral, prior repair, and length of postoperative stenting were not significant predictors of outcome. Overall, a successful outcome, without the need for biliary stents, was obtained in 98% of patients, including those requiring a secondary procedure for recurrent stricture. CONCLUSIONS: Major bile duct injuries and postoperative bile duct strictures remain a considerable surgical challenge. Management with preoperative cholangiography to delineate the anatomy and placement of percutaneous biliary catheters, followed by surgical reconstruction with a Roux-en-Y hepaticojejunostomy, is associated with a successful outcome in up to 98% of patients.

Adolescent↗

Sickness Impact Profile Score versus a Modified Short-Form survey for functional outcome assessment: acceptability, reliability, and validity in critically ill patients with prolonged intensive care unit stays.

BACKGROUND: Quality of life after surgical critical illness is an important measure of outcome. The Sickness Impact Profile Score (SIP) has been validated in critically ill patients, but the Modified Short-Form (MSF) has not been directly compared with it. METHODS: The SIP and MSF-36 were coadministered to 127 patients (surrogates) with a prolonged surgical critical illness at baseline at 1, 3, 6, and 12 months. Reliability, validity, and acceptability were determined for overall and subscores at each time point. RESULTS: The overall SIP and eight subscores, including physical health and psychosocial health, were all significantly improved at 1 year compared with baseline (p < 0.05). However, the MSF-36 was improved only in health perception (p < 0.05), but pain scores were higher (p < 0.05) than at baseline. Internal consistency of the MSF-36 was poor at 1 and 3 months. Correlation between the tools was excellent at baseline and 1 year but variable in overall and subscores at other time points. CONCLUSION: The SIP is more comprehensive, reliable, and acceptable in determining specific quality-of-life abnormalities, but the MSF-36 is easier to administer and correlates well at baseline and 1 year in patients with a prolonged critical illness.

Activities of Daily Living↗

Pulsed and parallel-polarization EPR characterization of the photosystem II oxygen-evolving complex.

Photosystem II uses visible light to drive the oxidation of water, resulting in bioactivated electrons and protons, with the production of molecular oxygen as a byproduct. This water-splitting reaction is carried out by a manganese cluster/tyrosine radial ensemble, the oxygen -evolving complex. Although conventional continuous-wave, perpendicular -polarization electron paramagnetic resonance (EPR) spectroscopy has significantly advanced our knowledge of the structure and function of the oxygen-evolving complex, significant additional information can be obtained with the application of additional EPR methodologies. Specifically, parallel-polarization EPR spectroscopy can be use to obtain highly resolved EPR spectra of integer spin Mn species, and pulsed EPR spectroscopy with electron spin echo-based sequences, such as electron spin echo envelope modulation and electron spin echo-electron nuclear double resonance, can be used to measure weak interactions obscured in continuous-wave spectroscopy by inhomogeneous broadening.

Cyanobacteria↗

T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen.

The fate of antigen-specific T cells was characterized in myelin basic protein (MBP) T-cell receptor (TCR) transgenic (Tg) mice after oral administration of MBP. Peripheral Th cells are immediately activated in vivo, as indicated by upregulation of CD69 and increased cytokine responses (Th1 and Th2). Concurrently, surface TCR expression diminishes and internal TCR levels increase. When challenged for experimental autoimmune encephalomyelitis during TCR downmodulation, Tg mice are protected from disease. To characterize Th cells at later times after antigen feeding, it was necessary to prevent thymic release of naive Tg cells. Therefore, adult Tg mice were thymectomized before treatment. TCR expression returns in thymectomized Tg mice 3 days after MBP feeding and then ultimately declines in conjunction with MBP-specific proliferation and cytokine responses (Th1-type and Th2-type). The decline correlates with an increase in apoptosis. Collectively, these results demonstrate that a high dose of fed antigen induces early T-cell activation and TCR downmodulation, followed by an intermediate stage of anergy and subsequent deletion.

Administration, Oral↗