Minimal Cellular Infiltration Research Articles

Clinical significance of in vitro donor-specific hyporesponsiveness in renal allograft recipients as demonstrated by the MLR.

A longitudinal study was carried out on 19 recipients of cadaveric renal allografts, monitoring their anti-donor and anti-third party responses in the mixed lymphocyte reaction (MLR) at the time of transplantation and at 3, 6, and 12 months post-transplant. Two patterns of responses were identified: in the first (n = 11), patients showed, or later developed, donor-specific hyporesponsiveness, and in the second (n = 8), patients had persistent antidonor and anti-third party responses. After 1 year, the serum creatinine, number of episodes of acute rejection and biopsy findings were compared in both groups. In the first group, the mean serum creatinine was 136.4 mmol/l, the total number of acute rejection episodes was three and in nine of the ten available biopsies, there were minimal cellular infiltrates and normal appearance of the glomeruli, tubules and blood vessels. In the second group, the mean serum creatinine was 163 mmol/l, the total number of acute rejection episodes was 12 and in five of the seven biopsies available, evidence of ongoing rejection was obtained. The difference in mean serum creatinine was not statistically significant (P > 0.05), but the difference in the numbers of acute rejection episodes was (P < 0.05). It is concluded that in some renal allograft recipients, a state of donor-specific hyporesponsiveness develops, and this state may be associated with better graft outcome at 1 year. These data may be useful in selecting patients for reduced immunosuppressive therapy.

IFN-gamma and IL-2 are protective in the skin but pathologic in the corneas of HSV-1-infected mice.

HSV type 1 (HSV-1) infection of the mouse cornea results in a tissue-destructive inflammatory reaction in the cornea, but little or no disease in the skin surrounding the eye. Depleting T lymphocytes from mice before HSV-1 corneal infection prevents the corneal inflammation but severely exacerbates the periocular skin lesions. Studies described in this communication investigated the role of T cell cytokines in the corneal and periocular skin disease induced by HSV-1 corneal infection. Mice received weekly i.p. injections of rat mAb specific for IL-2, IL-4, or IFN-gamma beginning 1 day before (day -1) or 6 days after (day +6) corneal infection with the RE strain of HSV-1. The severity of corneal inflammation and the area of periocular skin involvement were measured. Treatment with anti-IFN-gamma or anti-IL-2 significantly reduced the incidence and severity of corneal inflammation. Treatment was equally effective when initiated on day -1 (before T cell activation) or day +6 (after T cell activation but before the initiation of corneal inflammation). Treatment with anti-IL-4 had no effect. The histologic features of corneal inflammation in mock-treated mice included neovascularization, corneal edema, and cellular infiltration. Corneas of anti-IL-2-treated mice that developed inflammation had similar but less severe histologic features. Corneas of anti-IFN-gamma-treated mice that developed inflammation had neovascularization and edema but minimal cellular infiltration. Treatment with anti-IFN-gamma or anti-IL-2 significantly exacerbated periocular skin lesions when initiated at day -1, but not when initiated at day +6. Anti-IL-4 treatment had no effect on skin lesions. Treatment with either anti-IFN-gamma or anti-IL-2, when initiated at day -1, significantly inhibited the delayed-type hypersensitivity response to HSV Ag, but when treatment was begun at day +6 only anti-IFN-gamma significantly inhibited the delayed-type hypersensitivity response. Our findings suggest that IFN-gamma and IL-2 are important elements in both an immunopathologic T-lymphocyte response to HSV-1 Ag in the cornea and a protective T lymphocyte response in the skin.

Retroperitoneal fibrosis.

Retroperitoneal fibrosis is idiopathic in two thirds of cases and is found most commonly as an isolated fibrotic plaque centered over the lower lumbar spine and entrapping one or both ureters. It has been postulated that the fibrosis in the idiopathic cases results from a hypersensitivity reaction to antigens leaking into the retroperitoneum from atheromatous plaques in the aorta or common iliac arteries. In the remaining one third of cases, causes include ergot-derivative drugs, retroperitoneal hemorrhage or urine extravasation, and a desmoplastic response to a variety of tumors. In up to 15% of cases, associated fibrotic processes are found elsewhere in the body. Although the disease is imaged best with CT or MR, neither of these techniques can be used to differentiate benign from malignant plaques. Histologically, the disease is characterized in its early stages by inflammatory cells and edema in a loose collagen network. The mature plaque is composed of dense fibrous tissue with minimal cellular infiltration. This progression is important as it influences MR signal characteristics.

Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration

Three adult patients, two with undifferentiated connective tissue disease and one with carcinoma, had a distinctive pathologic reaction pattern consisting of necrotizing myopathy, minimal cellular infiltration, and a microangiopathy with thick "pipestem" vessels and microvascular deposits of complement membrane attack complex. Quantitative analysis revealed focal capillary depletion. This pattern represents an immune-mediated microangiopathy and is distinct from that observed in other inflammatory myopathies.

Central nervous system involvement in goats undergoing primary infections withTrypanosoma bruceiand relapse infections after chemotherapy

Relapse of infection after trypanocidal drug treatment of trypanosome infections is normally attributed to drug resistance on the part of the parasite, under-dosage of the drug, or reinfection of the host. We have demonstrated relapse infections in goats arising from none of these. Fourteen goats infected withTrypanosoma bruceisuffered severe illness and 3 died within 45 days. Despite treatment with the trypanocidal drug Berenil, a 4th goat died 2 days later. Recovery of the remainder followed chemotherapy, and in 2 goats, necropsiecl 45 days after treatment, no trypanosomes or abnormalities were detected. However 2–3 months after Berenil chemotherapy, despite trypanosomes being undetectable in the blood during the intervening period, infections in 4 of the remaining 8 animals relapsed. At all stages of the primary and relapse infections, trypanosomes isolated from the blood of the goats were completely susceptible to Berenil when tested in mice, as were parasites isolated from cerebrospinal fluid and brain tissue at necropsy. At the time of treatment, only minimal cellular infiltration was found in the central nervous system (CNS), but death from the relapse infection was associated with a very severe meningoencephalitis. We conclude that the relapse infections were caused by the re-emergence of trypanosornes from the CNS, where sequestered parasites were inaccessible to the trypanocidal effects of the drug.

Demonstration of mycobacterial antigens in nerve biopsies from leprosy patients using peroxidase-antiperoxidase immunoenzyme technique

Peripheral nerve biopsies from patients with leprosy were stained with anti- Mycobacterium bovis (BCG) in a peroxidase-antiperoxidase (PAP) system to demonstrate intraneural mycobacterial antigens. Most M. leprae antigens have been shown to crossreact with BCG. Of the 30 biopsies from borderline tuberculoid (BT) patients 18 had acid-fast bacilli while 26 of them had demonstrable mycobacterial antigens in their nerves. All borderline lepromatous (BL) and lepromatous leprosy (LL) nerve biopsies had both M. leprae and mycobacterial antigens within them. Most of the antigens in the BT patients were seen to be extracellular. In BL and LL patients antigens were seen both extracellularly and intracellularly in Schwann cells and infiltrating macrophages. Mycobacterial antigens in BT nerves were always seen to be surrounded by a mononuclear cell reaction while in the BL and LL patients antigens could be seen with minimal cellular infiltrate and the neural architecture was more or less preserved. While bacilli could not be seen in BT patients who had been released from treatment for more than 4 years, mycobacterial antigens could still be seen in some patients who had been released from treatment for up to 5 years. Patients with no skin lesions but with large, painful, or tender nerves were found to have intraneural inflammation surrounding mycobacterial atigens, while those with a similar clinical picture but without tender or painful nerves showed no marked inflammation within their nerves despite the presence of mycobacterial antigens. From these findings it was concluded that immunologically mediated inflammatory response toward intraneurally located M. leprae antigens in conjunction with other host factors may be necessary for nerve damage in the BT leprosy patients. In the BL and LL patients the mechanisms of nerve damage are still unknown with certainty but local effects and immune-complex damage secondary to abundant M. leprae antigens are worth exploring. The use of immunohistological techniques should offer a new approach in the study of the immunopathology of leprosy.

Residual heteroantigenicity of glutaraldehyde-treated porcine cardiac valves.

Treatment of porcine valves in vitro with glutaraldehyde significantly decreases their heteroantigenicity, as judged by immune reaction in mice heterografted with glutaraldehyde-treated valves or injected intraperitoneally with valvular homogenates. Conditioned porcine valves, grafted in a cutaneous pouch onto the backs of two different inbred strains (C57Bl and DBA) behave like inert material and show minimal cellular infiltration at histological examination. Little or no antibody response, demonstrate with the cytotoxicity test is elicited by glutaraldehyde-treated valvular tissue, either grafted or injected intraperitoneally as homogenate. These data supply a biological basis for the surgical practice of heterotransplants of glutaraldehyde-treated valves as an alternative to the artificial prostheses.

Effects of low- and high-passage influenza virus infection in normal and nude mice.

A human isolate of type A Hong Kong influenza virus (H3N2) was adapted to mice by serial passage. Lung homogenates from mice who received low passage levels contained about the same quantity of virus (10(6.2-6.95) 50% tissue culture infective doses/ml) as those from mice who received high passage levels (10(5.95-6.45) 50% tissue culture infective doses/ml); however, death occurred only in animals given high-passage virus. Passage 3 (P3) and passage 9 (P9) viruses were selected as representative of low-passage and high-passage viruses, respectively. Although minimal differences were detected in infectivity for rhesus monkey kidney tissue cultures and mice, P9 virus was at least 10,000 times more lethal for mice (mean lethal dose = 10(4.2)). Infection with P3 virus was accompanied by minimal bronchitis and bronchiolitis only, whereas P9-infected animals exhibited marked bronchitis, bronchiolitis, and pneumonia. Striking thymic cortical atrophy was also demonstrable in the P9-infected animals and, although virus was more commonly recovered from thymuses from these animals, immunofluorescent studies revealed only a few cells containing influenza virus antigens. To further explore the participation of thymus-derived lymphocytes in influenza, athymic nude mice and furred immunocompetent littermates were given 500 50% mouse infectious doses of P9 virus. Nude mice exhibited an increased survival time and, in contrast to the extensive lung pathology seen in furred littermates, manifested minimal cellular infiltration and no tissue destruction in lungs. Brains from nude mice exhibited encephalomalacia with lymphocytic perivascular cuffing, which was not seen in furred animals. Virus was recovered from brains of 6 of 13 nude mice and 1 of 10 furred animals. The contrasting models suggest that thymus-dependent cells play a significant role in the inflammatory response to influenza virus infection and should prove useful for probing host-virus interactions which characterize influenza virus virulence.

Proliferation of synovial lining cells and fibroblasts.

After in vitro incubation with 3H-thymidine, the proliferation of synovial lining cells and fibroblasts was investigated in surgically-removed articular tissue. Under normal conditions, in nonrheumatoid arthritis and in osteoarthrosis, low proliferation rates for both cell types were observed. In rheumatoid arthritis, the rate of proliferation of both cell types was usually increased. An increased proliferation of the synovial lining cells was especially observed in cases with a hyperplastic lining cell layer and in cases with a minimal lymphocytic and plasma cellular infiltration in the synovial membrane.

Beryllium disease: The relation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the U.S. Beryllium Case Registry

A group of 130 cases examined by biopsy or autopsy from the U.S. Beryllium Registry was reviewed and the histological findings in the lung correlated with the clinical course and prognosis. The appearance of the six acute cases studied was nonspecific, and it was impossible to correlate specific histological features with clinical course or intensity of exposure. The remaining 124 chronic cases were divisible into two moderately overlapping histological groups based on the degree of interstitial cellular infiltration. The largest group, representing 80 per cent of the total could be divided into two subgroups based on the absence or presence of a distinct granulomatous reaction. Although the mean course of illness in both subgroups was about eight years from the time of onset, 85 per cent of the first were already dead at the time of study, whereas only 60 per cent of the second had died. In contrast, the second group, representing 20 per cent of the total, showed minimal interstitial cellular infiltration and prominent granuloma formation resembling and often indistinguishable from sarcoidosis. In this group, the mean course to date was over 11 years and all but one patient was still alive. These findings suggest a distinct relation between the intensity of interstitial cellular infiltration and prognosis and may provide additional insight into the clinical behavior of patients presenting with a histological picture resembling sarcoidosis. No relationship could be found between the histological pattern and the effect of steroids, the character of the industrial exposure, or the length of the latent period prior to the onset of clinical symptoms.

Chronic kidney allograft reactions in rats.

SUMMARY Chronic rejection of orthotopic kidney allografts occurred between inbred Fischer and Lewis rats with survival times up to 48 weeks in Fischer ← Lewis combinations and greater than 60 weeks in Lewis ← Fischer combinations. Lewis recipients of Fischer kidney grafts showed prolonged survival in spite of repeated, prompt rejection of subsequent Fischer skin grafts. In otherwise normal Lewis recipients, chronic rejection of Fischer kidney allografts was characterized by minimal loss of renal function, slow but progressive destruction of kidney parenchymal tissue, and persistent alloantibody production until the terminal stages of rejection. Survival and function of Lewis ← Fischer kidney allografts were similar to that of isografts, however; there was minimal cellular infiltration and destruction of the allograft compared to the reciprocal combination. Lewis recipients, sensitized by Fischer skin or kidney grafts, showed accelerated rejection of subsequent Fischer skin grafts. Moreover, Lewis rats sensitized with Fischer skin grafts rejected subsequent Fischer kidney grafts in an accelerated manner. These findings demonstrated the reciprocal immunogenicity and vulnerability of kidney and skin allografts in these strain combinations. Nevertheless, kidney allografts between Lewis and Fischer rats had prolonged survival times, even though skin allografts were rejected promptly. Differential susceptibility to immunological enhancement mediated by humoral alloantibodies probably contributed to the disparate survival times observed. Functional, histological, and serological evidence support, this hypothesis.

Hyperacute rejection in human-kidney allografts -- Shwartzman or Arthus reaction?

Abstract The course of three patients indicated that both types of reaction, Shwartzman and Arthus-like, can occur in hyperacute rejection of human-kidney allografts and that the late histologic appearances may be indistinguishable. In the first patient hyperacute failure of the kidney occurred in four hours, in association with the development of a bleeding diathesis. Sequential histologic appearances were those of progressive fibrin deposition resembling a generalized Shwartzman reaction. In the second patient, two consecutive kidneys from the same donor were rejected within minutes of revascularization despite prophylactic heparinization. There was neutrophil infiltration without fibrin deposition. At four days there was cortical necrosis, fibrin thrombi in glomerular capillaries and minimal cellular infiltration. A third patient, without prophylactic heparin, showed both neutrophil infiltration and fibrin deposition at one hour and cortical necrosis at five days.