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Biomedical subjects

R B Colvin

Publications and source records attributed to R B Colvin.

At least 199 records · Page 11Linked to original sources
PubMed1983

Monitoring immunosuppression following renal transplantation.

Renal allograft recipients were given azathioprine and prednisone for immunosuppression following transplantation. In addition, pulses of steroids or courses of treatment with antithymocyte globulin (ATG) or PAN.OKT3 were employed to combat acute rejection episodes. Our results support the concept that ATG and PAN.OKT3 are useful in the treatment of acute kidney allograft rejection. In our experience, ATG often reversed acute kidney allograft rejection episodes and then provided relatively long-lasting immunosuppression with stable graft function. In contrast, PAN.OKT3 was more effective in reversing acute rejection, but subsequent rejection episodes occurred more frequently. In patients treated with PAN.OKT3, cells reacting with OKT3, OKT4 and OKT8 were removed from the circulation within minutes following the initial treatment, and the levels of these cells remained dramatically depressed during the first few days of treatment. Subsequently, peripheral blood cells which reacted with OKT4 or OKT8, but not OKT3, could be detected in most patients, even though treatment continued and excess circulating PAN.-OKT3 was present. Experiments in which these cells were cultured for 24 or 72 hr indicated that antigenic modulation by OKT3 had occurred in vivo. These results raise interesting questions about the mode of action of PAN.OKT3, and suggest that the combination of PAN.OKT3 with an agent which can establish long-lasting immunosuppression may be more effective than either agent given alone.

Antibodies, Monoclonal↗
PubMed1982

Fibronectin is produced by blood vessels in response to injury.

During the time of tissue repair that ensues subsequent to tissue injury, blood vessel wall fibronectin increases concomitantly with endothelial proliferation and angiogenesis. However, the source of this blood vessel fibronectin had not been delineated. In this report we have demonstrated that microvascular fibronectin is produced in situ by the proliferating vessels surrounding excisional wounds. This finding was established by extirpating 3 mm of skin from the center of a well-healed rat xenograph on the flanks of immunosuppressed mice, harvesting the injured skin sites at various stages during the healing process, and staining the specimens with reciprocal species-specific anti-fibronectin. The proliferating donor vessels that surrounded the wounded graft had increased fluorescence staining with FITC conjugated mouse anti-rat fibronectin and no staining with rat anti-mouse fibronectin. This finding was taken as direct evidence that the fibronectin was produced in situ by the rat vessels and not derived from circulating mouse plasma.

Animals↗
PubMed1982

Reduction of the fraction of circulating helper-inducer T cells identified by monoclonal antibodies in psoriatic patients treated with long-term psoralen/ultraviolet-A radiation (PUVA).

Ultraviolet radiation has been found to alter the distribution and function of human lymphocytes. To determine whether photochemotherapy (PUVA) alters circulating levels of T cell subset marker-bearing lymphocytes, cells from 9 patients with psoriasis undergoing PUVA therapy for several years (mean 4.6 +/- 1.4 yr), 17 patients with active untreated psoriasis, and 20 healthy volunteers were reacted with monoclonal antibodies to T cell surface markers, including OKT3 (all peripheral blood T cells), OKT4 (helper/inducer T cells), OKT6 (common thymocytes), and OKT8 (suppressor/cytotoxic T cells), and analyzed by flow cytometry. There were no differences in the distribution of T cell subsets between healthy volunteers and patients with active psoriasis. In contrast, the percentages of lymphocytes reacting with OKT3 and OKT4 were lower (by 16% and 12% percent respectively, p less than 0.0025) in the PUVA-treated patients compared to healthy volunteers or patients with active psoriasis that had not received PUVA therapy. There was no difference in the percentage of OKT8 and OKT6 bearing cells. Squamous cell carcinoma of the skin subsequently developed in 2 of 3 PUVA-treated patients with the lowest percentages of T4-bearing cells. These findings indicate that long-term PUVA therapy is associated with a reduction in circulating helper/inducer T cells. This reduction may have a role in the altered immune function reported in PUVA-treated patients.

Antibodies, Monoclonal↗
PubMed1982

Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization.

Factors regulating the attachment and directional migration of a regenerating epidermis in wound healing are poorly understood. In studies of guinea pig 4-mm skin wounds, left uncovered for 1-28 days, biopsied and processed for 1-micrometer section and immunofluorescence, the epidermis migrated over an irregular thickened provisional matrix containing fibrin and fibronectin. The provisional matrix lacked two major components of normal basement membrane, laminin and type IV collagen, which can mediate tenacious epithelial attachment to plastic in vitro and may limit epidermal cell migration in vivo. Upon completion of wound reepithelialization at 7-9 days after wounding, the basement membrane zone lost its thickened appearance, fibronectin and fibrinogen disappeared, and type IV collagen and laminin reappeared. Although these findings do not prove that epidermal cell migration during reepithelialization required a fibrin and fibronectin matrix, they demonstrate that epidermal cells do move over such a substratum during in vivo wound repair.

Animals↗
PubMed1982

Blood vessel fibronectin increases in conjunction with endothelial cell proliferation and capillary ingrowth during wound healing.

The regulation of angiogenesis and alterations in the structure of blood vessels taking part in wound healing are poorly understood. In studies of guinea pig 4-mm skin wound, left uncovered for 1-28 days, biopsied and processed for 1-micrometer section and immunofluorescence, we found that fibronectin in blood vessel walls markedly increased in conjunction with endothelial cell proliferation and capillary ingrowth. Both the endothelial cell proliferation and the increased vessel wall fibronectin were restricted to a 0.5-mm area along the margin of the wound and occurred 3-7 days after injury. Fibronectin was easily demonstrated in capillaries of the peripheral granulation tissue but was difficult to demonstrate in central areas of the granulation tissue secondary to a brightly fluorescent reticular background staining probably attributable to fibroblast-related fibronectin. The fibronectin in blood vessel walls rapidly diminished as endothelial cell proliferation and capillary ingrowth ceased. These data suggest that fibronectin may provide a provisional substratum for endothelial cell mitosis and movement.

Animals↗
PubMed1982

T-lymphocyte subsets in smoking and lung cancer: Analysis of monoclonal antibodies and flow cytometry.

In order to determine whether abnormalities of immunoregulatory T-cells occur in patients with lung cancer, we characterized peripheral T-lymphocytes in 26 patients with untreated lung cancer. The results in patients with primary squamous cancer (SC) (n = 10), primary adenocarcinoma (AC) (n = 7), and secondary lung metastases (M) (n = 9) were compared with each other and to subjects without cancer (n = 48), including nonsmokers (n = 29) and smokers (n = 19). We found that OKT3+ (mature, peripheral (T-lymphocytes, including both OkT4+ (inducer/helper) and OKT8+ (cytotoxic/suppressor) lymphocytes, were increased in light-to-moderate smokers, but that OKT4+ cells were decreased n heavy smokers (p less than 0.05). The ratio of OKT4+ to OKT8+ (4/8) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in light-to-moderate smokers, but was decreased in heavy smokers (p less than 0.05). The profile of circulating T-cells in patients with SC was similar to the smokers. In contrast, in patients with AC, we found a decreased percentage of OKT8+ cells (p less than 0.05). The 4/8 ratio was elevated in patients with AC (p less than 0.05). In patients with M, there was a decreased percentage of OKT3+ cells reflected in both OKT4+ and OKT8+ subsets. The 4/8 ratio in patients with M was low. Thus, a number of abnormalities in circulating T-cells was found both in smokers and in patients with lung cancer. These results suggest that immunoregulatory abnormalities contribute to the pathogenesis of lung cancer.

Adenocarcinoma↗
PubMed1982

Monoclonal antibodies to human T cell subsets: use for immunological monitoring and immunosuppression in renal transplantation.

Sequential monitoring of peripheral blood T cell populations was performed in normal control individuals and in 55 renal allograft recipients. In addition, 66 patients exhibiting prolonged renal allograft survival were each evaluated at least once with the same monoclonal antibodies. A normal or elevated OKT4:OKT8 ratio, especially in the presence of rising numbers of OKT4+ cells was predictive of possible future graft rejection. This observation, when followed by rising serum creatinine values coupled with biopsy evidence of glomerulopathy, was found in at least 15% of graft recipients. In a small number of patients, graft rejection episodes were successfully suppressed by administration of therapeutic doses of OKT3 antibody. However, production of anti-OKT3 antibodies was observed and may be expected to limit administration of this agent to a single short course in each patient.

Acute Disease↗
PubMed1982

Immunofluorescent staining with antibodies to factor VIII, fibronectin, and collagenous basement membrane protein in normal human skin and port wine stains.

Specific antibodies directed against three important components of the vessel wall (collagenous basement membrane protein-type IV collagen, fibronectin, and factor VIII) were used to study and compare the distribution of these proteins in normal skin and port wine stains. Collagenous basement membrane protein was localized to the basement membrane and basal lamina zones of blood vessels, appendages, arrector pili muscles, endoneurium and perineurium, and the dermoepidermal junction of both port wine stains and normal skin. Vessels of the port wine stain as well as those of normal skin showed a similar narrow uniform homogeneous line of fluorescence. Granular endothelial staining was seen in the blood vessels of both normal skin and port wine stains. The distribution of fibronectin was that of a low-intensity punctate pattern situated in the subendothelial region of both port wine stain and normal vessels and in the basement membrane zones of hair follicles, endoneurium and perineurium, and the dermoepidermal junction.

Adolescent↗
PubMed1982

Focal and segmental glomerulosclerosis and porteinuria associated with unilateral renal agenesis.

Because reduction of renal mass (nephrectomy) can promote the development of focal glomerulosclerosis in animals, we asked whether patients with unilateral renal agenesis might have similar lesions in the solitary kidney. We describe here the clinical course and pathologic findings of eight patients who developed focal and segmental glomerulosclerosis (FGS) in their solitary kidneys. A review of 586 surgical pathology renal specimens (452 biopsies and 134 nephrectomies) revealed 29 (4.9 per cent) cases of FGS; five also had unilateral renal agenesis (p = 2.1 x 10(-7)). In 9200 autopsies, seven cases of unilateral renal agenesis were found; two (29 per cent) died of chronic renal failure with FGS lesions, and five did not have FGS. The eighth patient was identified because he was the father of a patient in this series. At the time of diagnosis the median age of the patients with unilateral renal agenesis and FGS was 25 years; seven of eight were male. All had proteinuria; four had more than 3 gm. per 25 hours (range, 1.2 to 9.0 gm. per 24 hours). Six developed chronic renal failure, and four died of their renal disease. Two of the patients were related (father and son). One patient had clinical and morphologic evidence of reflux nephropathy. The glomerular lesions were characterized by focal and segmental scarring and adhesions in glomeruli, IgM and C3 deposition by immunofluorescence, and foot process loss and capillary loop collapse by electron microscopy. Our series, although small, indicates that patients with unilateral renal agenesis are significantly more likely to develop FGS than patients with two kidneys. In contrast, FGS did not develop after adult nephrectomy in 10 patients who died 8 to 46 years after adult unilateral nephrectomy. The reason for this association was not established; however, these findings are in accord with experimental studies in which subtotal nephrectomy in young animals promotes FGS. In that setting and in these patients, glomerular damage may result from glomerular overload.

Adolescent↗
PubMed1981

The vascular bed as the primary target in the destruction of skin grafts by antiserum. I. Resistance of freshly placed xenografts of skin to antiserum.

Rat skin grafted onto immunosuppressed mice is resistant to mouse anti-rat serum during the first 7-10 d after transplantation. It gradually acquires susceptibility, reaching a peak of sensitivity at 14-16 d after grafting. The grafts remain sensitive to antiserum, though at decreasing levels for an additional 3 wk, and grafts that persist beyond that time are resistant to antiserum for as long as they survive. In the study reported here, it is shown that the initial period of resistance to antiserum is due to factors acting locally within the graft and is entirely uninfluenced by the regimen of immunosuppression or the protective dressings that are used. After administration of antiserum, deposits of the injected immunoglobulin and of endogenous C3 are found on the luminal surfaces of graft vessels, although no significant tissue damage is observed. Rat skin that has become highly sensitive to antiserum 14-16 d after transplantation loses that sensitivity if it is regrafted to a new recipient, and then regains it 8-10 d later. Thus, the resistance of freshly grafted skin to antisera is associated with the process of healing into place, a conclusion that is supported by the observation that the intracutaneous administration of antisera to rats causes intense local inflammation and necrosis. The skin is therefore sensitive just before it is removed for grafting, but temporarily loses sensitivity thereafter. Resistance to antiserum during the first 3 or 4 d after transplantation is probably attributable to the fact that at that time grafts are vascularized poorly if at all. The state of resistance extends for several days after vascularization of the graft takes place and is then only gradually lost, a phenomenon that seems to be associated with the resistance of newly formed and regenerating blood vessels to vasoactive substances. This view is in accord with and, indeed, supports the idea that the induction of vascular injury is an essential step in antisera-mediated damage to tissue grafts.

Animals↗
PubMed1981

The vascular bed as the primary target in the destruction of skin grafts by antiserum. II. Loss of sensitivity to antiserum in long-term xenografts of skin.

Rat skin that survives for long periods of time on immunosuppressed mice becomes resistant to anti-graft serum and remains so for as long as it survives. When long-standing grafts are removed and placed on new immunosuppressed mice, they remain resistant to antiserum for as long as they survive. The acquired resistance to antiserum seems, therefore, to be due to changes in the grafts rather than to changes in their hosts. Furthermore, it was found that the acquisition of resistance is correlated with replacement of graft endothelium by host cells, as demonstrated by the use of immunofluorescent techniques in conjunction with mouse anti-rat serum and rat anti-mouse serum. Evidently, humoral antibodies are able to cause acute damage to skin grafts, and presumably to grafts to other organized tissues, only if they react with antigens of graft endothelium. Long-term grafts that are retransplanted to their original donors or to rats syngeneic with those donors are in most cases rejected, whereas 14-d-old grafts similarly regrafted are in no case rejected. Apparently, the responses of the secondary recipients to the mouse endothelial antigens in long-term grafts lead to destruction of the entire grafts. When long-standing rat skin xenografts are removed and placed on untreated mice syngeneic with the primary hosts, they are in every case rejected, although they survive slightly longer than skin taken directly from rat donors. Rejection is accompanied by a mononuclear infiltrate and is qualitatively indistinguishable from the rejection of freshly prepared rat skin. Clearly, sensitized cells are more efficient than humoral antibody in destroying grafted tissues.

Animals↗
PubMed1981

Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts.

Using monoclonal antibodies and flow cytometry, wer serially monitored lymphocyte subpopulations in renal-allograft recipients treated with either conventional immunosuppression or a monoclonal antibody. In 29 patients given conventional suppression, highly significant correlations between changes in T-cell subsets and rejection were noted. Normal or elevated ratios of OKT4 (helper/inducer) to OKT8 (suppressor/cytotoxic) cells were associated with rejection unless the donor was HLA identical or the total number of T cells was extremely low. In patients with low ratios, rejection seldom occurred. Two patients treated with OKT3 monoclonal antibody for acute rejection had rapid disappearance of OKT3-reactive cells from the peripheral blood and prompt reversal of rejection. The use of monoclonal antibodies allows the precise determination of changes in T-cell subsets and promises the development of therapeutic protocols that can be designed to manipulate selected lymphocyte populations.

Antibodies↗
PubMed1981

Glomerulopathy associated with cytomegalovirus viremia in renal allografts.

We investigated the relation between cytomegalovirus (CMV) infection and renal-allograft dysfunction in 14 patients. In seven instances (including two successive transplants in one patient), allograft dysfunction occurred during clinically manifest, viremic CMV infection. In five of these, biopsies revealed little or no tubulointerstitial change but a distinctive, diffuse glomerulopathy characterized by enlargement or necrosis of endothelial cells and accumulation of mononuclear cells and fibrillar material in glomerular capillaries. Two of these allografts recovered their function, both with cessation of high-dose immunosuppression. Biopsies in the other 10 patients revealed predominantly tubulointerstitial changes typical of cellular rejection, and most of these patients did not have viremia. One additional patient, studied prospectively, manifested both forms of allograft injury: tubulointerstitial changes occurring two weeks after transplantation and responding to increased immunosuppression, and CMV-associated glomerulopathy occurring seven weeks after transplantation and responding to decreased immunosuppression. We conclude that viremic CMV infection can cause acute glomerular injury and that recovery may be favored by a decreased in immunosuppressants.

Cytomegalovirus Infections↗
PubMed1981

The effect of infection on T lymphocyte subpopulations: a preliminary report.

The effect of cytomegalovirus (CMV) infection on T-lymphocyte subpopulations (employing the monoclonal antibody OKT4 to delineate helper cells and OKT8 for suppressor-cytotoxic cells) was studied in 10 normal individuals with CMV mononucleosis and four renal transplant patients with symptomatic primary CMV disease. In both clinical settings, acute CMV infection is associated with a reversal of the normal helper/suppressor-cytotoxic T cell ratio, with both a relative and absolute decrease in T helper cells and an increase in T suppressor-cytotoxic cells observed. With clinical recovery, there is a return of these cell populations toward normal ranges. In two patients, one with chronic CMV infection and one with chronic Epstein-Barr virus infection, the helper/suppressor-cytotoxic cell ratio was found to be reduced four years after the onset of infection. Five patients with febrile illnesses were also studied: two with viral infection and one with a self-limited febrile illness had decreased helper/suppressor-cytotoxic cell ratios, and two with bacterial infection had increased ratios. Thus, delineation of T lymphocyte subpopulations may be of value not only in evaluating the immunologic effects of a particular infectious agent, but also in the clinical evaluation of the febrile patient.

Animals↗
PubMed1981

Treatment of acute renal allograft rejection with OKT3 monoclonal antibody.

Eight cadaver donor renal allograft recipients, who had received azathioprine and prednisone from the day of transplantation, were treated with OKT3 monoclonal antibody (reactive with all mature peripheral blood T cells) at the time of diagnosis of acute rejection. In all cases, loss of essentially all detectable peripheral blood OKT3-reactive cells was noted within minutes after the initial 1- to 5-mg i.v. infusion. Chills and fever invariably occurred following the first or second infusion of monoclonal antibody, but were not noted during the subsequent, 10- to 20-day course of therapy, suggesting rapid cell lysis as the etiology of this toxicity. The established rejection episode was reversed in all cases within 2 to 7 days without addition of any therapy other than OKT3 antibody and despite continued lowering of the steroid dosages. During the subsequent 3- to 12-month follow-up period, further rejection episodes occurred in five of these patients, two of these were irreversible with conventional therapy so that six of the eight allografts continue with excellent renal function. These preliminary observations suggest that homogeneity, limited dosage requirements, and ease of in vitro monitoring of dosage effects should markedly simplify the use of monoclonal antibody to T cell populations in human allograft recipients. This second generation of antilymphocyte preparations offers the potential for not only increased effectiveness but also the possibility of manipulating specific T cell subsets.

Antibodies, Monoclonal↗
PubMed1981

Reactivity of a monoclonal antibody with human ovarian carcinoma.

A murine monoclonal antibody (OC125) has been developed that reacts with each of six epithelial ovarian carcinoma cell lines and with cryopreserved tumor tissue from 12 of 20 ovarian cancer patients. By contrast, the antibody does not bind to a variety of nonmalignant tissues, including adult and fetal ovary. OC125 reacts with only 1 of 14 cell lines derived from nonovarian neoplasms and has failed to react with cryostat sections from 12 nonovarian carcinomas.

Animals↗