Marked Lymphocytic Infiltration Research Articles

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

Sjögren's syndrome (SS) is an autoimmune disease that is characterized by infiltration of exocrine tissues, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Here, we show that mice with T cell-specific loss of class IA phosphoinositide 3-kinase function develop organ-specific autoimmunity that resembles the human disease SS. Most mutant mice aged 3-8 months develop corneal opacity and eye lesions due to irritation and constant scratching. These mice display cardinal signs of primary SS such as marked lymphocytic infiltration of the lacrimal glands, antinuclear antibodies in the serum, and elevated titer of anti-SS-A antibody, in the absence of kidney pathology. Immunofluorescence studies show the presence of numerous CD4+ T cells with a smaller number of CD8+ T cells and B cells in the lacrimal glands. CD4+ T cells from these mice exhibit aberrant differentiation in vitro. These results indicate that aberrant T cells with impaired class IA phosphoinositide 3-kinase signaling can lead to organ-specific autoimmunity. In addition, the mouse model described here represents a tool to study the pathogenesis and treatment of SS.

NOVEL NONHUMAN PRIMATE MODEL OF CELIAC DISEASE

Background: Celiac disease (CD) represents a unique model of autoimmunity in which a close genetic association with HLA genes, a highly specific humoral autoimmune response (autoantibodies to tissue transglutaminase, (TTG)), and, most importantly, the triggering environmental factor (gluten), are known. The lack of an animal model of the disease represents a major limitation in using CD as a research model of autoimmunity. Aims: To establish if pedigreed colony of baboons with hereditary chronic diarrhea could be used as a possible non-human primate model for CD. Methods: Baboons from the pedigreed colony at the Southwest Foundation for Biomedical Research were reviewed. Those animals with non-infective chronic diarrhea (≥21 days) and more than two clinical admissions between January 1998 and December 2003 were selected (N = 163). CD serology and intestinal histological analysis were performed on a selected number of animals. Results: Fifty-one of the 163 cases (31%) of chronic diarrhea occurred among the offspring of 4 sires. Of the 20 cases studied, 5 (25%) tested TTG IgA and/or IgG antibodies positive, compared to 1/17 (5.9%) in healthy control baboons. Zonulin, a modulator of intestinal permeability that is up regulated in CD, resulted elevated in 8/20 (40%) baboons with chronic diarrhea and 0/17 controls. There was 80% correlation between positive TTG IgG and elevated zonulin. Duodenal samples obtained after the baboons were euthanized showed increased intraepithelial lymphocytes and, occasionally, marked lymphocytic mucosal infiltration and villi distortion and blunting. Implementation of a gluten free diet resolved the animals' weight loss. Conclusions: Our preliminary data suggest that a gluten-dependent hereditary enteropathy is present in the progeny of a few sires of the baboon colony studied. The clinical, serological, and histological features suggest a similarity to human CD and, therefore, that the progeny of this sire can be potentially used as a primate non-human model of CD.

Transforming growth factor‐beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes

Colorectal cancers deficient in DNA mismatch repair (MMR) are often characterized by the presence of numerous intraepithelial lymphocytes (IELs). These CD8+ T cells selectively express CD103, which is upregulated locally by transforming growth factor (TGF)-beta, and adhere to E-cadherin expressed by mucosal epithelia. Many of these cancers also possess inactivating mutations in the type II TGF-beta receptor and are believed to be insensitive to TGF-beta. The present study aimed to explore whether such refractoriness to TGF-beta is an independently contributing factor to IEL retention. A panel of colorectal cancers enriched for DNA MMR deficiency was examined by immunohistochemistry to explore the expression levels and localization of various components in the TGF-beta signalling pathway. Logistic regression was then carried out in order to identify predictors of elevated lymphocytic infiltration independent of DNA MMR status. Increases in Smad4 expression, tumour cell proliferation and TGF-beta secretion each emerged as independent predictors of marked lymphocyte infiltration. These results strongly support the hypothesis that refractoriness to normal TGF-beta signalling in colorectal cancers plays a role in the retention of lymphocytes within tumour epithelium. Since IEL infiltration is an independent predictor of favourable prognosis, the TGF-beta pathway may represent an important therapeutic target.

Primary Palmoplantar Kaposi's Sarcoma: An Unusual Presentation

A 65-year-old diabetic Saudi Arabian man taking glibenclamide for 9 years presented with painful reddish patches and plaques involving the palms and soles of 6 months' duration. These lesions started as small faint purple-red macules and gradually increased in number and size. The patient did not seek any medical advice other than for these painful lesions. His medical history was insignificant. On examination, the patient had multiple, discrete, dull red-to-violaceous and tender patches and plaques of variable sizes on both palms and soles (Figure 1 and Figure 2). His mucous membranes, scalp, and nails were normal. A systemic clinical examination was unremarkable other than an amputation of the distal phalanx of the left index. Result of routine laboratory investigations including complete blood cell count, liver and renal function tests, and chest x-ray were normal. An HIV test was negative. A punch skin biopsy taken from the left palm showed acanthosis and spongiosis in the epidermis. The dermis showed a large number of dilated, medium-sized capillaries with scanty extravasated red blood cells, marked infiltration of lymphocytes and histiocytes, and a few plasma cells (Figure 3 and Figure 4). Immunohistochemistry results were positive for CD34 and CD68. Polymerase chain reaction for human herpesvirus 8 was also positive. The treatment options, including cryotherapy and intralesional chemotherapy, were discussed with the patient but, unfortunately, he did not return for follow-up.

A new model for limbal transplantation using E-GFP for follow-up of transplant survival

Limbal transplants in humans show a high rate of rejection even under local and systemic immunotherapy. In order to test immunomodulatory treatments a new limbal transplant model in the rat was developed using enhanced green fluorescent protein (E-GFP) as marker for follow-up. Sixty E-GFP-positive limbal transplants from Sprague–Dawley TgN(act-EGFP)Osb4 rats were transplanted onto 18 wild-type inbred Sprague–Dawley (isografts) rats, six wild-type litter mate Sprague–Dawley (sibling) rats, 18 Fischer 344 (allografts) rats, and 18 Fischer 344 rats depleted from monocytes and macrophages by subconjunctival treatment with clodronate liposomes. All rats were monitored three times a week with fluorescence microscopy, until fluorescence had disappeared. At postoperative days 6, 9, 12, and 15, three rats of all groups were killed for immunohistochemical analysis of infiltrating cells. Using a modified digital fluorescence microscope, we were able to monitor transplant behavior over time without disturbance of the ocular surface. The average days of rejection were 14 days in the isograft group, the sibling group, and the untreated allograft group. However, the average day of rejection in the allogeneic macrophage-depleted group was 27 days. Marked infiltration of macrophages and lymphocytes was seen in the untreated isografts and allografts. In the clodronate liposome-treated allografts infiltration was minor. A successful new limbal transplant model is described. The transplant can be accurately followed up in vivo by E-GFP labeling of the donor tissue without disturbing the corneal surface. Although E-GFP itself proved to be immunogenic, local clodronate liposome injections significantly increased graft survival. So the model seems to be useful for testing immunosuppressive or modulatory agents in limbal transplantation studies.

Temporal arteritis presenting with gastrointestinal symptoms in a middle aged man

Giant cell arteritis, also known as temporal arteritis, is a vasculitis of unknown etiology that classically involves the wall of the large to medium size. We are reporting a case of a young onset temporal arteritis presenting with gastrointestinal symptoms. The patient was a 48-year-old male who presented with a 2-week history of fever, diffuse abdominal pain, and malaise. He underwent a laparoscopic cholecystectomy after findings of elevated bilirubin and alkaline phosphatase as well as suspicion of porcelain gallbladder on ultrasound (or computed tomography scan). The patient subsequently developed painless, intermittent vision loss and unilateral headaches. A work-up included temporal artery biopsy, which showed marked lymphocytic infiltrate in the arterial wall consistent with temporal arteritis. The presentation of temporal arteritis may be atypical. We are reporting a case of temporal arteritis at a young age presenting mainly with gastrointestinal symptoms.

Jumbo biopsy is useful for the diagnosis of colonic prolapsing mucosal polyps with diverticulosis

We report here a case of multiple prolapsing mucosal polyps with diverticulosis in the sigmoid colon. A 52-year-old man was admitted to our hospital because of bloody diarrhea. Colonoscopy and barium enema showed multiple diverticula, markedly thickened mucosal folds and polypoid lesions with mucus on the top of them in the sigmoid colon. Endoscopic ultrasonography showed thickening of the mucosal and submucosal layers. Several endoscopic biopsy specimens were taken from the polypoid lesions. Histological examination revealed only chronic inflammatory cell infiltration. In order to obtain a definite diagnosis, we performed endoscopic jumbo biopsy for the polypoid lesions after obtaining informed consent. Histological examination revealed marked lymphocyte infiltration, hemosiderin deposits and fibromuscular obliteration in the lamina propria, features similar to those of mucosal prolapsing syndrome. After anti-diarrhetic treatment, clinical findings were improved. Thus, jumbo biopsy is useful for diagnosis and treatment of prolapsing mucosal polyps.

Immunohistochemical Detection of Apoptotic Proteins, p53/Bax and JNK/FasL Cascade, in the Lung of Rats Exposed to Cigarette Smoke

Lung disease is the leading and second-leading cause of death in women and men in Taiwan, respectively. Epidemiological studies conducted in Taiwan have shown that cigarette smoking is the principal risk factor of lung disease, but little is known about the association between apoptosis and cigarette smoke (CS)-induced lung pathogenesis. We designed an animal exposure system to study signal proteins involved in the process of apoptosis induced by smoking in rat terminal bronchiole. Rats were exposed to CS in doses of 5, 10, and 15 cigarettes, respectively, and the exposure lasted for 30 min, twice a day, 6 days a week for 1 month. Following which the rats were sacrificed and the lung tissues were analyzed by histopathological methods. The terminal bronchioles revealed mild to severe inflammation according to the doses of CS and marked lipid peroxidation, lymphocyte infiltration, congestion, and epithelial emphysema of alveolar spaces were also noted. Using an in situ cell death detection kit (TA300), the association of CS with apoptosis was determined in a concentration-dependent manner. Immunohistochemical evaluation showed that CS treatment produced an increase in the cellular levels of Bax, t-Bid, cleaved caspase-3, phospho-p53, phospho-JNK, and FasL but a decline in Bcl-2 and Mcl-1 (p<0.001 for all) in rat terminal bronchioles. The results provided evidences suggesting that exposure to CS not only induced apoptosis, but also involved p53/Bax and JNK/FasL cascade pathway.

Laparoscopic Resection of a Torsioned Appendix Epiploica in a Previously Appendectomized Patient

Torsion of the appendices epiploicae is a rare condition that may present with acute abdominal pain and mimics appendicitis. We report a 20-year-old previously appendectomized man presenting with right lower abdominal quadrant pain. Abdominal ultrasonography showed a localized omental thickening in the right paracolic region. Contrast-enhanced computed tomography revealed well-circumscribed fatty tissue adjacent to the cecum with heterogeneous hyperdense infiltration of the mesentery near the sigmoid colon. Diagnostic laparoscopy revealed 2-cm diameter torsioned and edematous fatty tissue floating on the omentum in the right lower quadrant. The torsioned mass was elevated, and a thick stalk was seen to be connecting the fatty tissue to the sigmoid colon. At this point, the torsioned fatty tissue was considered as a sigmoidal appendix epiploica that was elongated and neighboring on the previously operated-on region. The lesion was removed by laparoscopic means using 3 ports. Grossly, fat necrosis and internal bleeding were seen. Histopathologic analysis of the resected tissue demonstrated adipose tissue surrounded by fibrotic inflammatory changes with marked infiltration of numerous lymphocytes and histiocytes. In conclusion, torsion of appendices epiploicae should be included in the differential diagnosis of acute abdomen when evaluating patients with right lower quadrant pain and a history of appendectomy. Laparoscopic surgery provides definite diagnosis and prevents unnecessary open procedures for such lesions leading to peritoneal irritation.

Composite Tissue Allotransplantation: Development of a Preclinical Model in Nonhuman Primates

Composite tissue allotransplantation (CTA) has been recently introduced as a potential treatment for tissue loss secondary to burns, injuries, or resections. However, the optimal strategies to prevent CTA rejection remain undefined. Presently, no CTA model exists to evaluate human-specific immunosuppressants or the relative immunogenicity of all CTA tissues. We established a NHP CTA model utilizing a sensate osteomyocutaneous radial forearm flap that avoids functional impairment even in the case of graft loss. The model was evaluated in19 monkeys that underwent auto- or allotransplantation, with or without subtherapeutic immunosuppression to temporarily characterize rejection. Autografts showed no evidence of rejection. Nonimmunosuppressed allografts were rapidly rejected showing a perivenular T-cell infiltrate. This was associated with subsequent alloantibody formation and led to graft thrombosis without prominent dermal infiltration. Subtherapeutically immunosuppressed animals also developed alloantibody and rejected in a delayed fashion exhibiting a marked dermal lymphocytic infiltrate similar in magnitude and distribution to previously reported human cases. Our NHP model for CTA is well tolerated by NHPs, results in allosensitization, is responsive to immunosuppression, allows for the evaluation of CTA histology and can be used for the systematic preclinical evaluation of therapeutic maneuvers to improve allograft survival.

Aerosol Exposure to Western Equine Encephalitis Virus Causes Fever and Encephalitis in Cynomolgus Macaques

Cynomolgus macaques were exposed by aerosol to a virulent strain of western equine encephalitis virus (WEEV). Between 4 and 6 days after exposure, macaques had a significantly elevated temperature that lasted for 3-4 days. Clinical signs of encephalitis began as the body temperature decreased, and then they rapidly increased in severity. Cynomolgus macaques with clinical signs of encephalitis had elevated white cell counts in the blood caused mostly by increased numbers of segmented neutrophils and monocytes. Elevated serum glucose levels also correlated with the severity of the clinical signs of encephalitis. Three cynomolgus macaques died; immunohistochemical evidence of viral antigen was present in the brain and central nervous system (CNS). Microscopic analysis also revealed a marked lymphocytic infiltrate in the CNS. Cynomolgus macaques will serve as a useful model of aerosol exposure to WEEV for the evaluation of potential vaccine candidates.

Transgenic mice expressing the T cell antigen receptor specific for an immunodominant epitope of a major allergen of house dust mite develop an asthmatic phenotype on exposure of the airways to allergen

Current studies on mechanisms underlying allergen-induced pulmonary inflammation and asthma are hampered by the lack of appropriate physiological in vivo models that reflect the natural route of allergen exposure and sensitization. To generate and phenotype a transgenic mouse strain expressing the T cell receptor (TCR) specific for an immunodominant domain of the major inhalant allergen Dermatophagoides pteronyssinus species of house dust mite (Der p 1), for the development of an in vivo model of allergic asthma. Der p 1 transgenic mice were generated using TCR-alphabeta derived from a CD4+ T cell hybridoma reactive with Der p 1 residues p 110-131. The frequency and functional activity of peripheral T cells were determined and parameters of airway inflammation assessed following allergen challenge of the airways with Der p 1. CD4+ T cells are functionally active, exhibiting dose-dependent proliferation and IL-4 production on primary stimulation with Der p 1 or Der p 1, p 110-131 in vitro, independent of in vivo antigen priming. On sensitization of the airways with allergen, in the absence of systemic priming or the application of adjuvants, the TCR transgenic mice develop airway inflammation characterized by a marked lymphocytic and eosinophilic infiltrate with goblet cell hyperplasia and enhanced mucin production. The Der p 1 TCR transgenic mice provide a model for investigating the pathophysiological mechanisms of pulmonary inflammation following sensitization by exposure of the airways to allergen and for investigating the mode of action and efficacy of novel immunotherapeutics.

Lymphoepithelioma-Like Carcinoma of the Skin with Potential for Sweat Glandular Differentiation

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a cutaneous malignancy with histopathological resemblance to lymphoepithelioma of the nasopharynx. Its histogenesis remains unknown, and few cases showing skin appendage differentiation have been reported to date. We present the case of a 77-year-old Japanese male with an asymptomatic red nodule on his left cheek. Because the histopathological study revealed focal growth of tumor cells lacking connections with the epidermis and marked lymphocytic infiltration surrounding the neoplastic cell nests, the case was diagnosed as LELCS. On immunohistological staining, the neoplastic cells were positive for carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), multi-cytokeratin (CK), CK6, CK18, and CK19. On the basis of these results, we suggested that skin appendage differentiation, particularly sweat glandular differentiation, was present in this case.

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves’ ophthalmopathy treated successfully with glucocorticoids themselves

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves' ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Epstein–Barr virus myocarditis as a cause of sudden death: two autopsy cases

Although the Epstein-Barr virus (EBV) causes acute infection accompanied by a high fever in young people, there appears to be few reports of a fatal outcome involving myocarditis. We report two cases of unexpected sudden death due to acute myocarditis possibly caused by the EBV. They each visited a hospital due to common cold-like symptoms and unexpectedly died several days later. In both cases, autopsy revealed myocardial necrosis with marked lymphocytic infiltration. Polymerase chain reaction (PCR) screening was positive for the EBV, whereas immunohistochemistry and in situ hybridization for the EBV were negative. Serological investigations showed a mild elevation in antiviral capsid antigen IgG and anti-EBV nuclear antigen IgG in both cases. Immunohistochemical study of lymphocytic infiltrates showed strong positivity for a T-cell marker (CD45R0) in the myocardium and pharyngeal mucosa. These cases suggest the potential risk of mortality from acute EBV infection in young people, even without severe clinical manifestations, and the importance of microbiological investigations, including PCR procedures, in postmortem diagnosis of infectious diseases.

Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes—A clue to advent of pathological state in various organs of chronic hepatitis C patients

Osteopontin is a cytokine essential for initiation of Th1 immune reaction. We established transgenic mice expressing osteopontin in hepatocyte, in which liver necrosis with lymphocyte infiltration developed gradually from 12 weeks of age with up-regulated osteopontin levels in the circulation, suggesting that extrahepatic manifestations might also occur as a result of excessive Th1 immune reaction. We examined histological and immunohistochemical features of various organs in these mice. Splenomegaly and enlargement of lymph nodes around the liver and intestine became apparent with marked infiltration of small lymphocytes in the transgenic mice later than 24 weeks of age. Immunostaining revealed that lymphocytes in the spleen and lymph nodes were positive for either CD3 or CD20, suggesting that the infiltrating lymphocytes were both B and T cells. Similar lymphocyte infiltration was found in the lung, kidney and submandibular gland. Alveolar septa became hypertrophic with lymphocyte infiltration, and the lung showed the appearance of interstitial pneumonia. These lesions are similar to extrahepatic manifestations in chronic hepatitis C patients, suggesting that augmented Th1 immune reaction to hepatitis C virus (HCV) proteins or the proteins with molecular mimicry of HCV may be a contributing factor for the formation of the pathological state not only in the liver but also in various organs under chronic infection of hepatitis C virus.

Multiple granulomatous inflammation in the minor salivary glands: A proposed new entity, allergic granulomatous sialadenitis

We report a patient who presented with multiple small submucosal nodules with granulomatous inflammation in the minor salivary glands of the oral cavity. A 43-year-old woman presented with a 1-week history of multiple small submucosal nodules in her oral cavity after having taken medicine for abdominal pain. The patient did not have a history of fever, rectal bleeding, skin lesions or arthritis, but did have a history of drug allergy and bronchial asthma. Histopathological examination of the submucosal nodules showed sialadenitis with marked infiltration of lymphocytes, eosinophilic cells, macrophages and Langhans-type or foreign-body-type multinucleate giant cells. The macrophages tended to be aggregated and appeared to have caused immature granuloma formation without caseous necrosis. Degranulated eosinophilic cells were numerous. Sarcoidosis, Crohn's disease, tuberculosis and atypical mycobacterial infection were not identified by medical examination. Three weeks after discontinuing the medication the patient was seen again at a follow-up visit. Multiple submucosal small nodules and other symptoms were not evident at that time. This case report may represent a new entity of salivary gland disease that we tentatively refer to as 'allergic granulomatous sialadenitis'.

COMPOSITE TISSUE ALLOTRANSPLANTATION: DEVELOPMENT OF A NON-HUMAN PRIMATE MODEL.

P653 Introduction: Composite tissue allotransplantation (CTA) is an emerging field requiring an amalgamation of microsurgical technique and immunosuppressive management. Although the technical aspects of CTA have followed logically from replantation, the discipline remains immunologically undefined. Specifically, it has not been established whether CTA rejection follows a predictable pattern through the many transplanted tissues, nor has it been determined whether some tissues are immunodominant or perhaps spared immune attack. Furthermore, of the immunosuppressants available for use in CTA, many have human specificity and cannot be evaluated in small animals. Based on an evaluation of specimens from transplanted human limbs, we have recently introduced a classification system to standardize CTA rejection. We have shown that vasculitis, dermatitis, myositis and perineural involvement can be seen during rejection, but given the sporadic availability of human tissue, the progression of the immune response remains undefined. Aims: To permit systematic study of the progression and resolution of CTA rejection, we have established a non-human primate (NHP) model. NHPs provide anatomical, antigenic and immunological similarity to humans, and can be used to test most human-specific biological agents. Limb transplantation in NHPs could markedly impair their social development. We have therefore designed our model to incorporate all elements of a limb CTA yet leave no functional deficit even in the case of rejection or excision. Methods: Our model involves a transplanted radial forearm flap including bone, muscle, nerve, tendon, artery, vein and skin. To validate this model, 5 animals have undergone autotransplantation and 11 have received allografts with and without immunosuppression (subtherapeutic tacrolimus, mycophenolate and prednisone to allow for rejection to be temporally characterized). Donor-recipient pairs for CTA were selected based on MHC non-identity, blood type and size. Results: The procedure was well tolerated by all animals and had no adverse functional consequences. The model allows for protocol biopsies to be performed without threatening the viability of the flap. Autografts showed no evidence of rejection and served as the baseline for CTA comparison. Non-immunosuppressed allografts showed an infiltrate initially arising within 3 days in the perivenular tissue leading to graft congestion and failure without a prominent dermal infiltrate. Subtherapeutically immunosuppressed animals rejected in 2 weeks with a marked dermal lymphocytic infiltrate similar in magnitude and distribution to human cases seen to date. Conclusions: We have established a NHP model for CTA that is responsive to immunosuppression and allows for the systematic evaluation of CTA histology and therapeutic maneuvers to improve allograft survival.

CHARACTERIZATION OF HUMAN AND NON-HUMAN PRIMATE COMPOSITE TISSUE ALLOGRAFT REJECTION.

O127* Introduction: Composite tissue allotransplants (CTAs) differ from other vascularized allografts in their embryologically diverse tissues. Given the infrequent application of CTA, it has not been established whether rejecting tissues have an immunological hierarchy. Aims: We have examined specimens from transplanted human limbs in various stages of rejection and compared them with a more controlled evaluation of rejecting non-human primate limb CTAs to determine the temporal progression of CTA rejection and evaluate the relative degree to which CTA elements are targeted for immune destruction. Methods: Human tissues were received from international transplant centers for histological evaluation. A primate radial forearm flap model was developed for serial histological and transcript RT-PCR analysis. Primate autografts (n=5) and allografts with (n=7) and without (n=4) subtherapeutic immunosuppression have been studied with protocol incisional and excisional biopsies. Primate CTA components studied included native and donor skin, skeletal muscle, artery, vein, nerve and tendon. Results: Human CTA rejection under immunosuppression presented as a rash localized to the allograft, and was characterized by a prominent dermal infiltrate. Given that biopsies were prompted by skin signs, this could indicate that rejection begins in the dermis, or that rejection becomes clinically evident after the infiltrate reaches the dermis. Primates evaluated without immunosuppression had an infiltrate arising within 3 days in the perivenular tissue leading to graft congestion and failure without a prominent dermal infiltrate. Dermal findings were consistent with ischemic injury referable to the early vascular injury. Subtherapeutically immunosuppressed animals rejected in 2 weeks with a marked dermal lymphocytic infiltrate similar to human cases. The inflammatory lesions in the engrafted tissues were primarily perivascular and CD3+. Levels of mRNA of most composite tissues showed constituative expression of the regulatory cytokines IL-10 and TGF-B. These increased in native tissues exposed to trauma and in rejecting tissues suggestive of local regulation in response to tissue injury. Allografts were unique in their expression of CD80, CD25, and T-bet consistent with a cytotoxic T-cell mediated event. This was most evident in transplanted artery and skin. Conclusions: Thus, the clinical appearance of a rash occurs relatively late as an extension of vascular alloimmune egress. These data suggest that protocol surveillance of CTAs may be of some benefit in detecting occult alloimmune activity.

Autoimmune Thyroid Disease

Autoimmune thyroid disease is common and was the first autoimmune disease to be described, based on observations in animals immunized with thyroid extract and adjuvant. There are several different clinical presentations which, although being distinctive, share some common features in terms of genetic susceptibility, environmental factors that predispose to disease and pathogenic features such as the presence of autoantibodies against thyroglobulin and thyroid peroxidase. In autoimmune hypothyroidism, the thyroid is initially enlarged due to the presence of a marked lymphocytic infiltrate; this phase is followed by fibrosis, atrophy of the gland, and failure to synthesize normal levels of thyroid hormones. The main etiological factors in this process are cytotoxic T cells and an intrathyroidal proinflammatory state created by local cytokine release. Humoral autoimmunity may contribute through the action of thyroid-stimulating hormone (TSH) receptor-blocking autoantibodies or through the activation of complement and antibody-dependent NK cell-mediated cytotoxicity. In Graves' disease, thyroid overactivity is caused by autoantibodies which stimulate the TSH receptor. T cells which recognize the receptor also localize to the orbit in many of these patients, as a subpopulation of fibroblasts at this location also express the receptor; the cytokines produced by these T cells in turn leads to the clinical features of Graves' ophthalmopathy.