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Biomedical subjects

L N Martin

Publications and source records attributed to L N Martin.

At least 55 records · Page 3Linked to original sources
PubMed1991

Thymus in simian immunodeficiency virus-infected rhesus monkeys.

The thymuses from 20 simian immunodeficiency virus (SIV)-infected and 4 uninfected rhesus monkeys were examined at intervals after infection to determine whether there were specific SIV-induced lesions, to document the serial distribution of SIV antigens, mRNA, and DNA, to quantitate the number of infected cells, and to correlate thymic changes with other parameters of infection. The following techniques were used: gross pathology, histopathology, immunohistochemistry, electron microscopy, in situ hybridization, polymerase chain reaction, and limiting dilution culture. Thymic involution due to loss of lymphocytes was apparent 8 weeks after inoculation. No epithelial damage or loss of Hassall's corpuscles was observed. Culture was the most sensitive technique for detecting SIV, being positive in 19 of 20 inoculated monkeys. The polymerase chain reaction was negative in one thymus that was positive at a low level by culture. In situ hybridization was positive in 14 of 19 thymuses examined, with a few macrophages in the cortex having a strong signal and numerous lymphocytes in the medulla having a weak signal. Mature viral particles and viral budding could not be demonstrated by electron microscopy. The number of cells positive for viral RNA by in situ hybridization correlated with the level of serum antigenemia. These observations suggest that thymic macrophages and lymphocytes are infected with SIV within 2 weeks after inoculation. SIV apparently directly causes loss of thymic lymphocytes and immunodeficiency without infecting or damaging the thymic epithelium. No specific SIV-induced lesions were recognized. The number of cells in the thymic medulla expressing SIV RNA correlates with the level of serum antigen, which has been previously shown to be correlated with disease progression.

Animals↗
PubMed1991

Infection of rhesus monkeys with topical instillation of simian immunodeficiency virus (SIV)B670 into the conjunctival sac.

We tested the ability of SIV to cause local and systemic infection in three rhesus monkeys after topical instillation of cell-free virus into the conjunctival cul-de-sac. Conjunctivitis or other signs of infection were monitored after inoculation. Conjunctiva were swabbed for virus culture and biopsied for PCR. Changes in lymphocyte subsets, seroconversion, antigenemia, and virus isolation from PBL were assessed systemically postinoculation. Viral DNA was detected in conjunctival biopsy by PCR in one of three animals that later developed systemic infection. The other two animals remained uninfected. These data demonstrate that the conjunctiva is a route by which SIV (and perhaps HIV) may cause systemic infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Serial pathogenesis study of SIV brain infection.

A serial study of early SIV brain infection revealed initial involvement of leptomeninges, followed by perivascular infection of brain parenchyma. Severity of SIV encephalitis correlated with severity of systemic disease rather than with length of infection. Diffuse white matter disease was not observed, and there was little evidence of SIV infection of brain endothelial cells. SIV infection of leptomeninges is separate from infection of the brain, which appears to be due to transvascular spread of infected monocytes/macrophages.

Animals↗
PubMed1990

Pathology of dual Mycobacterium leprae and simian immunodeficiency virus infection in rhesus monkeys.

Three rhesus monkeys were experimentally inoculated with sooty-mangabey-derived Mycobacterium leprae and were inadvertently infected with the simian immunodeficiency virus (SIV) as well. They died of an immunodeficiency syndrome, and at autopsy all had lesions caused by M. leprae. One monkey was inoculated twice with M. leprae, initially with an inoculum from a sooty mangabey that was not infected with SIV and, subsequently, with an inoculum from a mangabey that was SIV infected. The monkey did not develop clinical lesions and became strongly lepromin skin test (LST) positive after the first inoculation, but became infected with both agents and LST negative following the second inoculation. These observations suggest that SIV-infected rhesus monkeys have an increased susceptibility to M. leprae infection and, by analogy, imply that HIV-infected human beings may have an increased susceptibility as well.

Animals↗
PubMed1989

A formalin-inactivated whole SIV vaccine confers protection in macaques.

A vaccine against human immunodeficiency virus (HIV) would be highly effective in stopping the acquired immunodeficiency syndrome (AIDS) epidemic. A comprehensive evaluation of potential vaccine methodologies can be made by means of the simian model for AIDS, which takes advantage of the similarities in viral composition and disease potential between simian immunodeficiency virus (SIV) infection of rhesus macaques and HIV infection in humans. Immunization with a formalin-inactivated whole SIV vaccine potentiated with either alum and the Syntex adjuvant threonyl muramyl dipeptide (MDP) or MDP alone resulted in the protection of eight of nine rhesus monkeys challenged with ten animal-infectious doses of pathogenic virus. These results demonstrate that a whole virus vaccine is highly effective in inducing immune responses that can protect against lentivirus infection and AIDS-like disease.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Interactions between simian immunodeficiency virus and Mycobacterium leprae in experimentally inoculated rhesus monkeys.

Thirty-four rhesus monkeys were inoculated with Mycobacterium leprae inoculum isolated from sooty mangabey monkeys with leprosy. Later it was learned that one of the M. leprae-donor mangabeys was asymptomatically infected with simian immunodeficiency virus (SIV). Thus, five of the rhesus monkey were coinoculated with M. leprae and SIV. Three of the five became SIV-positive and developed signs of leprosy and an AIDS-like illness. Two animals remained healthy. The coinoculated leprosy-positive rhesus monkeys developed leprosy despite serologic response patterns to M. leprae antigens that usually indicate leprosy resistance. Three (60%) of the five SIV-positive rhesus monkeys developed leprosy compared with 21% of the animals who received SIV-free M. leprae inocula. Diminished lepromin skin test responses and decreasing T-helper cell percentages were observed in SIV-coinoculated rhesus monkeys with leprosy. These observations suggest that SIV increases the susceptibility of rhesus monkeys to leprosy, possibly related to loss of T-helper cell function.

Animals↗
PubMed1989

Experimental arthropathy induced in rhesus monkeys and DBA/1 mice by a novel method: intraperitoneal implantation of type II collagen adsorbed onto nitrocellulose filters.

A novel method which avoids the use of complete Freund's adjuvant (which can be arthritogenic) has been used to induce collagen II arthritis in both primates and mice. A solution of bovine type II collagen was dried onto nitrocellulose filters and implanted in the peritoneal cavity of experimental animals. Primate and mouse joints were scored by clinical as well as gross and microscopic parameters. The polyarthritis that developed in both rhesus monkeys (Macaca mulatta) and DBA/1 LAC J mice was characterized by synovial cell proliferation and endothelial cell hyperplasia, and by a perivascular mononuclear cell infiltrate of the synovium. Primates were analyzed further for anti-type II collagen antibody titers and delayed type hypersensitivity to type II collagen. Anti-type II collagen serum titers appeared to be unrelated to the disease pathology; the primates did not display delayed-type hypersensitivity to type II collagen. Control monkeys and mice implanted with collagen-free nitrocellulose filters were normal upon clinical and histopathological analysis. This protocol offers the advantage of the induction of arthritis due solely to immunization with antigen.

Animals↗
PubMed1988

Simian immunodeficiency virus/delta-induced immunodeficiency disease in rhesus monkeys: relation of antibody response and antigenemia.

Infection of the rhesus macaque (Macaca mulatta) with simian immunodeficiency virus (SIV) induces a disease similar to AIDS. We compared SIV-specific antibody and antigenemia with the progression of disease in monkeys experimentally infected with SIV/Delta isolates that varied in pathogenicity. Western blot, immunoprecipitation, and sandwich enzyme-linked immunosorbent assay of serial sera from macaques infected with attenuated virus revealed a persistent antibody response and no evidence of SIV antigenemia. Immunosuppressed macaques without central nervous system (CNS) infections responded similarly to initial infection, but antibody specific for gag or, less frequently, to gag and env determinants declined predictably before clinical disease. Monkeys with CNS infections, however, had little, if any, detectable antibody to either envelope or gag proteins, regardless of the duration of survival. SIV/Delta-specific antigenemia, evident only in immunodeficient monkeys, fluctuated reciprocally with antibody. Our data suggest that SIV/Delta-induced disease is dependent upon antigenemic episodes that, particularly in animals with CNS infection, appear coincident with diminished antibody.

Animals↗
PubMed1988

Necropsy findings in rhesus monkeys experimentally infected with cultured simian immunodeficiency virus (SIV)/delta.

Lesions induced in rhesus monkeys by different isolates of simian immunodeficiency virus (SIV)/Delta were studied at necropsy. Four groups of monkeys were inoculated with SIV/Delta isolated from other experimentally infected rhesus monkeys, while one group was inoculated with SIV/Delta from an asymptomatic mangabey monkey. Three rhesus isolates and the mangabey isolate were virulent, killing 75-100% of infected monkeys. One rhesus isolate, which had been extensively passaged in vitro, was attenuated but was restored to virulence by single animal passage. Clinically, infected monkeys had lymphadenopathy, splenomegaly, diarrhea, and a rash. Most monkeys died of enteric disease. The following lesions were seen: weight loss, thymic atrophy, lymphoid atrophy, bone marrow hyperplasia, encephalitis, colitis, amyloidosis, hepatitis, glomerulosclerosis, and the presence of syncytial cells. One Rh Epstein-Barr virus (EBV)-related lymphoma occurred. Opportunistic agents were identified: cytomegalovirus, adenovirus, Cryptosporidia, and Pneumocystis. Shigella and Campylobacter often caused colitis.

Animals↗
PubMed1988

Histopathological changes in the eyes of mangabey monkeys with lepromatous leprosy.

Leprosy is the third leading cause of preventable blindness; however, little is known about the spread of infection to the eye. We have studied the eyes of three sooty managabey monkeys. Two were experimentally infected with Mycobacterium leprae; the third was not infected. In one of the infected animals there was histopathological evidence of lepromatous leprosy as evidenced by a chronic inflammatory infiltrate at the limbus, and detection of acid-fast bacilli in the corneal stroma, blood vessel walls, and corneal nerves. The latter were damaged as a result of the bacillary invasion. Electron microscopy revealed involvement and distortion of keratocytes with M. leprae and invasion of the corneal stroma by macrophages containing bacilli. Both infected animals showed focal collections of lymphocytes in the superficial stroma of the conjunctiva and in the ciliary body. This is the first report of the ocular manifestations of leprosy in any primate, including man, in which the duration of infection is known.

Animals↗
PubMed1987

Lepromin-induced lymphoproliferative response of experimental leprosy monkeys: regulatory role of monocyte and lymphocyte subsets.

We investigated the immunological status of seven normal, control Mangabey monkeys and 23 Mangabey monkeys experimentally inoculated with Mangabey-origin Mycobacterium leprae. Clinically, these monkeys were divided into three broad groups: a recently inoculated group, a resistant group, and a susceptible group. The resistant group included 11 monkeys, seven of which showed no clinical sign of disease to date and four of which had shown local disease that partially regressed spontaneously. The susceptible group included eight monkeys, five of which have disseminated disease and three with local but stable disease. When peripheral blood mononuclear cells of these monkeys were cultured with Dharmendra-type human lepromin, one of seven normal monkeys, four of four of the recently inoculated group, seven of 10 resistant monkeys, and three of eight susceptible monkeys showed significant responses. In this experimental monkey model, we studied possible regulatory mechanisms by using OKT4- and OKT8-enriched lymphocytes, and Fc receptor-positive (FcR+) and FcR- monocyte (M phi) subsets. The OKT4+ subset was the main lepromin-responsive cell type. High percentages of OKT8+ cells showed a good negative correlation with the lymphoproliferative responses of T-enriched cells supplemented with unfractionated M phi. But the depletion of OKT8+ cells could not increase the response of nonresponding monkeys' lymphocytes. The resistant group and susceptible group did not differ in their percentages of OKT8+ cells. Because OKT8+ cells negatively regulate the response of lymphocytes and OKT4+ cells are the main responding cells, OKT8+ cells are phenotypically and functionally suppressor cells and OKT4+ cells are the helper/inducer cell population in this system. The FcR- M phi population mainly includes antigen-presenting activity, but high percentages of FcR- M phi showed a significant negative correlation with lymphoproliferative responses in the resistant group. A weak but significant lymphocyte response to Dharmendra lepromin was obtained by depleting FcR+ M phi from cultures of some susceptible monkeys, whereas lymphocytes of other susceptible monkeys remained unresponsive to lepromin. By these criteria, we could find an array of immunological defects in monkeys with experimental leprosy. The data suggest that some immunological defects may exist in the OKT4+ lymphocytes or FcR- M phi of leprosy monkeys.

Animals↗
PubMed1987

Experimental leprosy in African green monkeys (Cercopithecus aethiops): a model for polyneuritic leprosy.

Three African green monkeys (Cercopithecus aethiops) were inoculated intravenously and intracutaneously with Mycobacterium leprae derived from a naturally infected mangabey monkey. All developed cutaneous lesions at inoculation sites. One developed disseminated cutaneous lesions, while the cutaneous lesions in the other two regressed and eventually disappeared. The animals were examined at necropsy five years after inoculation. All three had active leprosy infection in peripheral nerves with extensive inflammation and fibrosis. The disease histologically resembled borderline-lepromatous leprosy. These findings add a new dimension to animal models of leprosy.

Animals↗
PubMed1987

Regulatory role of FcR+ and FcR- monocyte subsets in Mycobacterium leprae-induced lymphoproliferative response in vitro.

We investigated nine rhesus monkeys (Macaca mulatta) inoculated with Mycobacterium leprae and three normal human contacts. Peripheral blood monocytes were separated into Fc receptor positive (FcR+) and Fc receptor negative (FcR-) fractions, and their regulatory role in the lymphoproliferative response in vitro to M. leprae was studied. FcR- monocytes had strong antigen presentation activity and produced no suppressor effect while FcR+ monocytes had weak antigen presentation activity and produced a non-specific suppressor factor spontaneously. With this assay system we determined that M. leprae-inoculated rhesus monkeys could be divided into three groups: good responders, very weak responders, and non-responders.

Animals↗
PubMed1987

Experimental leprosy in a rhesus monkey: necropsy findings.

A 6-month-old male rhesus monkey (Macaca mulatta) was inoculated intravenously and intracutaneously with Mycobacterium leprae obtained from a naturally infected mangabey monkey. The animal developed generalized lepromatous leprosy, and was killed for pathological examination 56 months after inoculation. Lesions were observed in the skin, nasal mucosa, peripheral nerves, and peripheral lymph nodes, with relative sparing of viscera. The monkey was carefully evaluated for the retrovirus STLV-III infection and was found negative. The rhesus monkey thus provides another animal model for the study of leprosy.

Animals↗
PubMed1987

Experimental arthropathy induced in rhesus monkeys (Macaca mulatta) by intradermal immunization with native bovine type II collagen.

Over a 6-month time course, polyarticular arthritis was induced in 7 male rhesus monkeys by 3 intradermal injections of bovine type II collagen emulsified in complete Freund's adjuvant, followed later by 2 intradermal injections of type II collagen in incomplete Freund's adjuvant. All animals exhibited delayed-type hypersensitivity to type II collagen by skin test and had serum anti-type II collagen titers of greater than 10,000 (at 1 month) and 20,000 to 160,000 (at 6 months) by enzyme-linked immunosorbent assay. Gross joint changes were observed in 6 of 7 monkeys, especially in the knee and elbow; synovial cell hyperplasia, increased vascularization and a focal mononuclear cell infiltrate were the most frequent findings. Chronic arthritis with destructive cartilage lesions was most prominent in the phalangeal joints of the hands (7 of 7 animals). Microscopically, these changes consisted of fibrosis of the synovium with increased vascularization, villous synovial membrane hyperplasia and focal mononuclear cell infiltration, as well as fibrous metaplasia of the articular cartilage adjacent to pannus formations. Also evident was a loss of safranin O staining intensity in the cartilage and loss of continuity of the articular surface. The 7 control monkeys (received Freund's adjuvant without collagen) were delayed-type hypersensitivity-negative, had no serum anti-type II collagen antibodies, and had grossly and microscopically normal joints. This primate model resembles collagen-induced arthritis seen in rodents and, to some degree, human rheumatoid arthritis.

Animals↗