N. W. King

Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody.

Recent studies have demonstrated the induced expression of endothelial adhesion molecules including E-selectin (also called endothelial leukocyte adhesion molecule-1), vascular cell adhesion molecule and intercellular adhesion molecule in actively involved mucosa of patients with ulcerative colitis and Crohns disease. Similar induction has been demonstrated in the colon of the Cotton-top tamarin (CTT), a New World primate that experiences a spontaneous acute and chronic colitis resembling ulcerative colitis. To assess the potential importance of leukocyte adhesion as a necessary step in acute colitis, the effect of parenteral mAb directed against adhesion molecules on CTT colitis was evaluated in placebo-controlled blinded trials. Serial administration of either of two anti-E-selectin mAb designated BB11 and EH8 effectively coated endothelial surfaces expressing this vascular adhesion molecule. Although colitis activity was slightly diminished after the 10-d treatment period in CTT receiving either BB11 or EH8, this reduction was not significantly different than that seen in animals given a placebo control when assessed by a previously validated standardized scale of inflammatory activity: mean histologic activity grade 2.2 +/- 0.2 pretreatment vs 1.5 +/- 0.5 posttreatment in group receiving mAb and 2.1 +/- 0.1 pretreatment vs 1.3 +/- 0.5 posttreatment in the placebo group (P > 0.2). In contrast, administration of an anti-alpha 4 integrin mAb designated HP1/2 that binds VLA4 (alpha 4 beta 1) and presumably alpha 4 beta 7 integrins resulted in significant attenuation of acute colitis when compared to both pretreatment activity index (P = 0.005) and the placebo control group (P < 0.01): mean histologic activity grade 1.6 +/- 0.3 pretreatment vs 0.2 +/- 0.1 posttreatment in the group receiving HP1/2 and 1.8 +/- 0.5 pretreatment and 1.2 +/- 0.2 posttreatment in the placebo control group. These studies using a model of spontaneous colitis in the CTT demonstrate the feasibility of modulation of leukocyte-vascular adhesion and/or other integrin-mediated events possibly including T cell aggregation and T cell-stromal interactions, as well as lymphocyte homing. These results suggest both that these processes are important and possibly essential elements in sustaining acute colitis and that their disruption may result in therapeutic benefit.

Expression of vascular adhesion molecules in inflammatory bowel disease

The expression of the vascular adhesion molecules ELAM-1 (endothelial leukocyte adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) was evaluated in colonic mucosa of patients with inflammatory bowel disease and normal controls by immunocytochemistry. VCAM-1 was found to be constitutively expressed in lymphoid aggregates in normal colonic mucosa and was not significantly enhanced or altered in distribution in mucosa of patients with inflammatory bowel disease regardless of the activity of the inflammatory process. In contrast, ELAM-1 was not detected by these techniques in normal colonic mucosa (n = 11) or in colonic mucosa of patients with inflammatory bowel disease which was either uninvolved or quiescent (n = 30). However, high levels of ELAM-1 were consistently found on endothelial surfaces in association with active inflammation in affected areas of colonic mucosa in patients with either ulcerative colitis (n = 27) or Crohns colitis (n = 9). In addition, ELAM-1 appeared to be present within neutrophils which had migrated into crypt abscesses in affected mucosa. Similar analysis was carried out in the cotton-top tamarin (CTT), a primate that experiences an idiopathic chronic diffuse colitis resembling human ulcerative colitis. Although anti-human VCAM-1 antibodies did not react with the CTT, anti-human ELAM-1 stained endothelial surfaces in mucosal biopsies from CTT with active colitis. No ELAM-1 was identified in mucosa of CTT in which colitis activity was quiescent. Thus ELAM-1 is expressed on colonic endothelial surfaces in association with inflammation and may play an important role in facilitating leukocyte migration into sites of active IBD involvement.

Long-term persistent infection of macaque monkeys with the simian immunodeficiency virus.

Juvenile rhesus macaques 6 to 18 months of age were experimentally infected by intravenous inoculation with the simian immunodeficiency virus (SIV), the T cell-tropic retrovirus of monkeys related to the human acquired immunodeficiency syndrome (AIDS) virus HIV. The SIV used for inoculation was grown either in normal human peripheral blood lymphocytes in the presence of interleukin 2 or in the human tumour cell line HUT-78. Eight of the macaques died 129 to 352 days post-inoculation with a variety of clinical and pathological findings paralleling those of AIDS in humans. However eight other animals became persistently infected for prolonged periods; these eight macaques remained alive at 537 and 820 days post-inoculation despite persistent lymphadenopathy and our continued ability to isolate SIV. The ability of these monkeys to survive infection correlated directly with the strength of their antibody response to SIV. Infection was also established in macaques using approximately 100 tissue culture infectious doses of HUT-78-grown SIV. There was no correlation between the dose of virus inoculum and either the strength of the antibody response or clinical outcome. These results demonstrate that SIV infection of macaques can be used not only to study acute AIDS but also to mimic the long-term persistent infection seen in carriers of HIV.

Characterization of Spontaneous Colitis in Cotton-Top Tamarins (Saguinus oedipus) and Its Response to Sulfasalazine

Chronic colitis in the cotton-top tamarin (CTT) has been characterized by obtaining distal colonic biopsy specimens, hematocrits, serum albumins, and stools for bacteriologic and parasitic examination in nondebilitated living CTTs. The species specificity of the histologic features of colitis observed in the CTT was assessed by obtaining distal colonic biopsy specimens from 10 animals of other primate species for histologic examination. Histologic evidence of active colitis was found in 50% of adult CTTs but was absent in all non-CTT species studied. Forty-two stool samples obtained from 18 CTTs yielded only one isolate (Campylobacter). In addition to active colitis, CTT rectal mucosa also often had subtle irregularities in mucosal structure that were not present in nonrelated primate species and might represent chronic colitis. Metaplasia was not observed. The therapeutic effects of oral sulfasalazine (50 mg/kg X day) on CTT colitis were assessed in a randomized 10-wk placebo controlled crossover study. This study demonstrated significant improvement in disease activity as judged histologically (p less than 0.05) and significant increases in animal weight (p less than 0.01) and serum albumin (p less than 0.01) during sulfasalazine therapy when compared with saline control. Sulfasalazine therapy can ameliorate the effects of this disease and offers promise in maintaining experimental colonies of this endangered species for future studies.

Humoral immune responses to T cell tropic retrovirus simian T lymphotropic virus type III in monkeys with experimentally induced acquired immune deficiency-like syndrome.

The T cell tropic retrovirus of macaque monkeys simian T lymphotropic virus type III (STLV-III) has morphologic, growth, and antigenic properties indicating that it is related to human T cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), the etiologic agent of the acquired immune deficiency syndrome (AIDS) of humans. STLV-III has recently been shown to induce an AIDS-like disease in macaque monkeys. In this study the humoral immune responses of six experimentally infected monkeys have been characterized to determine whether certain parameters of the antibody response to the virus might be predictive of the clinical outcome of this infection. Two distinct patterns of antibody responses were found. Four animals that died within 160 d of inoculation developed low titer anti-STLV-III antibody responses that recognized only the viral envelope protein, and progressive declines in total plasma IgG levels and absolute peripheral blood T4 lymphocyte numbers. The two animals that lived longer (one died at 352 d, the other remains alive at 430 d) developed high titer anti-STLV-III antibody responses that recognized both viral envelope and core proteins, increases in total plasma IgG, and a later decrease in number of peripheral blood T4 lymphocytes. Interestingly, the single animal that has remained clinically healthy after infection was the only one to develop detectable STLV-III neutralizing antibodies.

Colonic Mucin Composition in Primates: Selective Alterations Associated With Spontaneous Colitis in the Cotton-Top Tamarin+

Heterogeneity of colonic mucin glycoprotein was examined in rectal mucosal biopsy specimens from a variety of primate species (Saguinus oedipus, n = 18; Macaca mulatta, n = 2; Macaca fascicularis, n = 2; Aotus trivirgatus, n = 2; Saimiri sciureus, n = 2; and Callithrix jacchus, n = 2). After initial separation of radiolabeled mucin and nonmucin glycoproteins solubilized from mucosal biopsy specimens, at least five labeled mucin components were found in monkey rectal mucosa in contrast to the six mucin fractions observed in the human colon. Although primates consistently lacked the earliest eluting component present in human colonic mucin, other mucin components cochromatographed with comparable fractions previously identified in human colonic biopsy specimens. The relative proportions of each fraction were consistent throughout all species except the cotton-top tamarin (S. oedipus), an animal that develops a chronic colitis. The cotton-top tamarin was found to have a markedly reduced amount of one mucin component (IV) in a manner analogous to the reduction in a human mucin fraction previously noted in patients with ulcerative colitis. Sequential evaluation of mucin profiles in cotton-top tamarins (n = 12) treated with sulfasalazine (50 mg/kg X day) or placebo in a 10-wk double-blind crossover study demonstrated the persistence of the selective reduction in tamarin species IV unrelated to disease activity. In contrast, the relative amount of tamarin mucin III was greater in association with increased disease activity than that observed in association with reduced disease activity (46% +/- 11% total mucin vs. 19% +/- 7% total mucin posttreatment).

Nephritis and hemolytic anemia in owl monkeys (Aotus trivirgatus).

The two most common diseases of captive owl monkeys (Aotus trivirgatus) are hemolytic anemia and glomerulonephritis. The anemia is characterized by total red blood cell counts between 0.45 and 3.44 × 106/μl, hemoglobin values as low as 1.0 g/dl, and many circulating nucleated red blood cells. Centrilobular necrosis in the liver, extramedullary hematopoiesis in liver and spleen, and hemoglobin casts in kidney tubules are prominent histologic features. Hemosiderin and lipofuscin often are found in liver, spleen, kidney and lymph nodes. Microthrombi and microinfarcts sometimes are scattered throughout the brain. Glomerular lesions in Aotus have been described previously and are characterized by increased numbers of mesangial cells and matrix, glomerulosclerosis and electron dense deposits in basement membranes. Lymphocytes, plasma cells and eosinophils frequently are present in the interstitium. In the early stages the cellular infiltrate is periglomerular. The foci then grow to encompass adjacent glomeruli and tubules. Finally, large portions of the kidney are affected and connective tissue proliferates. The incidence of extramedullary hematopoiesis in the liver correlated significantly with that of interstitial nephritis (0.001 < p < 0.01) but not with glomerular lesions. The two kidney lesions, glomerulonephritis and interstitial nephritis, correlated strongly in incidence. They also were found with equal frequency in 87 monkeys with clinical evidence of anemia. This analysis indicates that there may be no common pathogenesis of the hematologic and renal abnormalities as seen in certain autoimmune diseases. However, there could be complex interactions between two or more disease mechanisms that account for the various manifestations of disease.

Simian Models of Acquired Immunodeficiency Syndrome (AIDS): A Review

Reports of the unprecedented occurrence of Kaposi’s sarcoma and fatal Pneumocystis carinii pneumonia in previously healthy homosexual men in New York and California in 198 1 heralded the onset of the current human epidemic known as the acquired immunodeficiency syndrome Since those initial reports, the incidence and spread of this disease have increased dramatically. Individuals affected with AIDS develop a prodrome of generalized lymphadenopathy, referred to as lymphadenopathy syndrome, frequently culminating in a selective and profound depression of cellmediated immunity that thus far appears irreversible. Typically, this immunodeficiency is characterized by a reversal of the ratio of T4 + (helper-inducer) to T8 + (suppressor-cytotoxic) subsets of lymphocytes in the peripheral circulation, impairment of delayed cutaneous hypersensitivity and decreased responsiveness of T-lymphocytes to in vitro mitogen stimulation. Patients with AIDS frequently develop life-threatening infections with one or more of the following opportunistic pathogens: Pneumocystis carinii, Cryptococcus neoformans, Toxoplasma gondii, Candida albicans, Mycobacterium tuberculosis, Mycobacterium aviumintracellulare, cytomegalovirus (CMV), Herpesvirus hominis (simplex), adenoviruses and papovaviruses. In addition, Kaposi’s sarcoma and Burkitt’s-like lymphoma occur with much greater frequency in AIDS patients than in the general population. Although initially confined to certain high-risk groups that included promiscuous male homosexuals, intravenous drug-abusers, Haitians, hemophiliacs, and blood transfusion receipients, AIDS is being increasingly recognized in patients that do not belong to any of these groups. It is now well established that the disease can be transmitted through both homosexual and heterosexual contact through use of contaminated hypodermic needles and blood products, and from infected mothers to their newborn children. Early epidemiologic evidence strongly suggested that AIDS was caused by a transmissible agent. In 1983, a retrovirus variously termed lymphadenopathy-associated virus (LAV), human T-lymphotropic virus type I11 (HTLV111) or AIDS-associated retrovirus (ARV) was isolated and shown to be the cause of AIDS.2,39,45 This agent will be referred to as HTLV-III/LAV in this review. Interestingly, HTLV-III/LAV has been shown to have a number of biological characteristics in common with several viruses of ungulates classified in the lentivirus subfamily of retroviruse~.~~~ ~~ These agents include maedi-visna virus (MVV), caprine arthritis-encephalitis virus (CAEV) and equine infectious anemia virus (EIAV). Recently, HTLV-III/LAV has been shown to be neuropathic and associated with dementia and a characteristic granulomatous encephalitis in adult as well as pediatric patients.

Isolation of Herpes-T virus from a spontaneous disease in squirrel monkeys (Saimiri sciureus)

Herpes-T virus was isolated from 2 of 4 clinically ill squirrel monkeys. The clinical manifestations of the disease in the monkeys was characterized by oral and labial lesions. From one of two animals sacrificed for histopathological examination, Herpes-T virus was isolated from the tongue and salivary gland. Herpes-T was isolated from the oral swab of one of the two live monkeys on the day of arrival in our laboratory and again on the 4th day. The anal swabs collected from both these monkeys failed to yield virus. The sera of these monkeys collected on the day of arrival showed a neutralization index (NI) of 1.0 and 1.5 against Herpes-T virus. The convalescent sera, collected two weeks later, showed a NI of 3.5 and 4.0 respectively for the same virus. Clear plaques ranging in size from 2 to 3 mm were produced in chick fibroblast and rabbit kidney primary monolayers. This is the first report of the isolation of Herpes-T virus from naturally infected squirrel monkeys. This data further supports that the squirrel monkey is a natural host of Herpes-T virus.

Family history as a risk factor for ulcerative colitis–associated colon cancer in cotton-top tamarin

BACKGROUND & AIMS Little is currently known about the relationship between family history of colon cancer and ulcerative colitis-associated colon cancer. A nested case-control study was performed to evaluate the association between family history of colon cancer and spontaneously occurring colon cancer in cotton-top tamarins (Saguinus oedipus). METHODS Subjects were chosen from a colony of cotton-top tamarins held in captivity between 1968 and 1995. The cancer status of parents and grandparents was compared for 48 animals with colon cancer and 58 controls, all with histological confirmation of ulcerative colitis. Multivariate odds ratios were calculated using logistic regression. RESULTS A parental history of colon cancer was positively associated with risk of colon cancer (multivariate odds ratio, 2.7; 95% confidence interval, 1.1-6.3). Risk also increased as an animals total number of family members with colon cancer increased (multivariate odds ratio, 1.7 for each increase in the total number of family members with cancer; 95% confidence interval, 1.1-2.8). CONCLUSIONS The results suggest that cotton-top tamarins with ulcerative colitis are at significant increased risk for developing colon cancer if they have a family history of colon cancer. Further investigation of this relationship in both tamarins and humans is warranted.