T-dependent destruction of thyroid isografts exposed to IFN-gamma.

Several autoimmune diseases are accompanied by tissue-specific expression of class II molecules of the MHC, and it has been suggested that this elicits a T cell response against tissue-specific Ag to which the individual is not tolerant. However, recent transgenic studies have indicated that non-lymphoid expression of class II genes in the pancreas, liver, and kidney is either innocuous or induces peripheral tolerance. To test this hypothesis in another organ-specific autoimmune disease, we attempted to induce autoimmune thyroiditis in normal mice with class II+ thyroid tissue. Normal thyroid lobes were cultured with and without IFN-gamma and then transplanted to adult isogeneic recipients. The thyroid that had been induced to express class II genes by IFN-gamma was destroyed in normal mice, whereas the control cultured thyroid and the native cervical gland survived. Both types of transplants remained intact and functional in congenic nu/nu recipients, indicating that neither exposure to IFN-gamma nor expression of class II genes compromised the thyroid. Thus, in some tissues, exposure to IFN-gamma and/or the induction of class II expression can lead to T-dependent autoimmune disease.

Airway compromise after carotid surgery in patients with cervical irradiation.

Symptomatic carotid atherosclerotic disease occurring as a result of cervical irradiation often requires surgical intervention. Airway obstruction is an uncommon problem after most carotid surgery and has not been described for patients with cervical irradiation. Airway obstruction developed after two of five carotid endarterectomy procedures in previously irradiated necks requiring emergency tracheostomy or reintubation. Mechanisms of obstruction included endotracheal tube trauma to the fixed irradiated vocal cords and laryngeal edema caused by surgical dissection in an irradiated field. In addition, one patient in our series demonstrated hypercarbia as a result of bilateral carotid body ablation, a process known to impair the ventilatory response to hypoxia. An increased risk of airway obstruction after carotid surgery exists in patients with prior cervical irradiation. Preventive methods include the use of perioperative steroids and either carotid surgery with local anesthesia or bronchoscopic vocal cord visualization and intubation.

Surgery for radiation-induced symptomatic carotid atherosclerosis.

Carotid atherosclerosis occurring secondary to cervical irradiation is known to produce stroke. Transient neurologic symptoms have necessitated surgical intervention to prevent stroke despite concern over technical problems, wound healing, operative risks, and uncertain therapeutic outcome. With this report, 26 surgical procedures in 20 patients are now documented in the literature (12 men--60%; eight women--40%). Mean age of these patients (56 years) was 10 years younger than carotid surgery patients with no prior radiation history. No relationship was noted between elevated serum cholesterol and the subsequent development of radiation-induced carotid atherosclerosis. Surgical procedures performed included carotid endarterectomy in 17 cases (65%) and arterial bypass in nine (35%). The combination of radiation therapy and previous neck surgery, including prior radical neck dissection, did not adversely influence operability. Surgical outcome was uniformly good with only one stroke (4%) documented in the perioperative period. Longer follow-up on our six cases (mean two years) disclosed neither new clinical symptoms nor the development of hemodynamically significant restenosis.

Elevated levels of a lymphocyte subset accurately predict the diabetic state in the BB rat.

The frequency of Ia antigen bearing W3/13 positive lymphocytes from the blood of 68 bio-breeding (BB) diabetes-prone rats was analyzed with monoclonal antibodies to determine whether elevated levels of these cells could predict which animals would subsequently become hyperglycemic. Selecting a value of greater than or equal to 4.00% as elevated, the sensitivity of this assay in predicting diabetes was 85%, while the specificity was 83%. We believe that elevated levels of Ia antigen bearing W3/13 positive lymphocytes reflect an ongoing immune process and accurately predict the likelihood of developing spontaneous hyperglycemia when obtained from a high risk population.

Immunologic studies of the prediabetic stage in the spontaneous autoimmune diabetes mellitus of the BB rat.

Twenty-eight BB diabetes-prone rats underwent prospective analysis to determine levels of circulating Ia antigen-bearing "activated" T lymphocytes prior to 50 days of age using mouse antirat monoclonal antibodies OX6 (anti-Ia) and W3/13 (anti-T-cell) and a fluorescence-activated cell sorter. Pancreatic biopsies were obtained within 48 hrs of lymphocyte sampling and histologically examined for the presence of a lymphocytic infiltrate. Elevated levels of "activated" T lymphocytes (above 4.00%) accurately identified a prediabetic stage and predicted which BB rats would subsequently become diabetic (93% sensitivity). The insulitis lesion occurs in the latter portion of this immunologically defined prediabetic stage just prior to the development of hyperglycemia. This observation suggests that islet cell destruction represents the final focus of a chronic immune response.

The influence of T-lymphocyte precursor cells and thymus grafts on the cellular immunodeficiencies of the BB rat.

To determine whether abnormal T-lymphocyte precursor cells or an abnormal thymus is responsible for the immunologic deficiencies of spontaneously diabetic BB rats, thymus grafts or T-cell-depleted bone marrow cells were exchanged between diabetes-prone and non-diabetes-prone animals. Analysis of peripheral lymphocyte populations from these recipients with monoclonal antibodies, a fluorescence activated cell sorter, and mixed lymphocyte culture tests indicate that an abnormal thymus is not responsible for the immunodeficiency of BB rats, but that the defect resides within the lymphocyte precursor pool.

The influence of ultraviolet irradiation on the blood transfusion effect.

Reports of improved survival of allografts in recipients of donor-specific blood prompted an attempt to determine the relationship of the antigenic composition of the blood product transfused to the development of immunologic unresponsiveness in rats. Cardiac allografts were transplanted from Fischer, Brown-Norway (BN), and Lewis (L) X BN (LBN) f1 hybrids to recipients treated with three weekly transfusions of 1 ml of donor-specific whole blood, erythrocytes, or ultraviolet-irradiated whole blood. Despite moderate improvement in survival with whole blood alone in the LBN- greater than L group (11.6 +/- 1.0 days), it was only with the ultraviolet-irradiated whole blood that marked prolongation was seen in all three strain combinations: Fischer- greater than L: 25.5 +/- 5.2, LBN- greater than L: 17.3 +/- 1.2, and BN- greater than L: 11.1 +/- 0.4 days compared with respective controls: 10.3 +/- 1.2, 7.3 +/- 0.5, and 7.4 +/- 0.6 days. Unlike reports for renal allografts, erythrocyte suspensions provided minimal protection for the cardiac allografts (14.2 +/- 0.8, 9.0 +/- 1.1, and 11.0 +/- 0.4 days, respectively), and adjunctive treatment with antilymphocyte serum had a similar small effect (16.3 +/- 1.4, 13.4 +/- 1.9, and 8.3 +/- 0.8 days, respectively). The elimination or inactivation of functional class 2 major histocompatibility complex antigens from the blood used for donor-specific blood transfusion may be an effective means of prolonging allograft survivals over those seen with whole blood alone; however, the degree of resultant unresponsiveness is still clearly influenced by dosage schedule, the organ transplanted, histocompatibility barrier, and adjunctive immunosuppression.

"Activated" T-lymphocyte levels in the spontaneously diabetic BB rat syndrome.

About 50% of individual members of a diabetes-prone stock of BB rats eventually become hyperglycemic (usually between 60 and 180 days of age) while the remainder remain normoglycemic for life. Circulating levels of Ia antigen bearing T-lymphocytes from different lymphoid compartments of acutely diabetic and normoglycemic (but diabetes prone) BB rats were determined with monoclonal antibodies in an effort to analyze the temporal relationship between levels of this unusual T cell antigen and the onset of diabetes. In young normoglycemic rats elevated blood levels of Ia-positive T-lymphocytes (greater than or equal to 4.00%) predicted the future development of hyperglycemia with a sensitivity of 85% and a specificity of 83%. The interval between the identification of these elevated levels and the onset of diabetes ranged from 22 to 82 days. After the development of hyperglycemia the level of Ia-positive T-lymphocytes declined progressively in all lymphoid compartments with chronicity of the diabetes. We conclude that Ia antigens bearing T cells serve as immunologic "markers" of susceptibility to diabetes in this "high-risk" population and probably reflect an ongoing immune process during the prediabetic state. Similar findings in humans with a family history of diabetes might lead to identification of prediabetic individuals and allow selective use of immunomodulation to prevent the disease.

Increased incidence of Ia antigen-bearing T lymphocytes in the spontaneously diabetic BB rat.

The frequency of Ia-positive T lymphocytes in spontaneously diabetic BB rats was assessed by using monoclonal antibodies and a fluorescence-activated cell sorter. These cells peaked in frequency during the early stages of hyperglycemia, with a gradual decline toward normal as the disease progressed. Significantly increased numbers of Ia-positive T cells were detected in both helper (W3/25+) and cytotoxic-suppressor (OX8+) subsets. The elevated levels of Ia-positive T lymphocytes in these rats may be relevant to the immune destruction of their beta cells.

Noninvasive techniques in the assessment of lower-extremity arterial occlusive disease. The advantages of proximal and distal thigh cuffs.

We studied 209 limbs angiographically and noninvasively to determine whether measurements of upper-thigh (UT) and lower-thigh (LT) segmental pressures (four-cuff technique), combined with segmental pulse-volume recordings (PVRs), offered any advantage over the standard single-thigh cuff (three-cuff technique) and PVR in the diagnosis of aortoiliac (AI) and superficial femoral artery (SFA) occlusive disease. Angiographic stenosis of 50% or greater and occlusions were considered to be hemodynamically significant lesions in this study. In the absence of SFA disease, sensitivity to AI disease was high (96%) and not significantly different using three- or four-cuff measurements. However, in the presence of SFA-segment disease, four-cuff measurements, both with and without PVR, were significantly more sensitive to AI disease (100%) and more specific for a normal AI segment (76%) than the three-cuff, PVR technique. Plethysmography alone was most sensitive to SFA disease (90%), even in the presence of AI disease, and sensitivity was not improved by additional segmental pressure measurements. The four-cuff system enhances the physician's ability to diagnose AI disease in the presence of SFA lesions, while PVR is most useful in detecting SFA lesions in the presence of AI disease.