Cellular differentiation and the aging process in cartilaginous tissues. Mucopolysaccharide synthesis in cell cultures of chondrocytes.

Primary cell cultures of differentiated chondrocytes were shown to produce chondroitin-4-sulfate as the predominant mucopolysaccharide, with suggestive evidence for the synthesis of keratan sulfate and possibly chondroitin-6-sulfate. Chicken embryonic cartilage was shown to be composed mainly of chondroitin-4-sulfate, with a small amount of chondroitin-6-sulfate, but essentially no keratan sulfate. These findings were compared to the data of others, and a hypothesis explaining the aging process in cartilage in terms of cellular differentiation was presented.

Integrating regional and community lung cancer services to improve patient care.

Lung cancer is the leading cause of cancer death in Canada. The organization of health care services is central to the delivery of accessible, high-quality medical care and may be one factor that influences patient outcome. An exciting opportunity arose for clinicians to initiate the redesign of lung cancer services provided by three institutions in the Greater Toronto Area. This qualitative report describes the integrated lung cancer network that they developed, the innovation it has facilitated, and the systematic approach being taken to evaluate its impact. Available clinical resources were deployed to restructure services along patient-centred lines and to provide greater access to the specialist lung cancer team. A non-hierarchical clinical network was established that consolidates the lung cancer team. A multi-institutional and multidisciplinary tumour board and comprehensive thoracic oncology clinics are at its core. This innovative organizational paradigm considers all of the available services at each facility and aims to fully integrate specialists across the three institutions, thereby maximizing resource utilization. We believe that this paradigm may have wider applicability. The network is currently working to complete a current program of further service improvements and to objectively assess its impact on patient outcome.

Monoclonal antibody therapy of spontaneous AKR T-cell leukemia.

We have previously shown that monoclonal antibodies against the Thy 1.1 differentiation antigen can inhibit the outgrowth of a lethal inoculum of transplanted AKR T-leukemic cells. In the present report we have extended these studies to examine antibody therapy of aged AKR/J mice with spontaneous leukemia. Infusion of anti-Thy 1.1 antibody in frankly leukemic mice led to uniform early mortality from cell lysis and agglutination. In contrast, anti-Thy 1.1 antibody therapy of mice in remission following treatment with cyclophosphamide prolonged remission duration (P less than 0.001) and modestly prolonged survival (P less than 0.01) compared to treatment with irrelevant antibody or chemotherapy alone. The major cause of failure was relapse of leukemia. In 85% (47 of 55) of cases relapse was due to cells that continued to express Thy 1.1, but in 15% of these relapsing animals all leukemic cells failed to express the target antigen. Our results suggest that monoclonal antibody against a normal T-cell antigen can add to the antileukemic effects obtained with chemotherapy alone. Nevertheless, the clinical benefit of unmodified antibody was modest, and antibodies conjugated to cytotoxic agents may be needed to overcome the limitations of unmodified antibodies.

Experimental radiotherapy of murine lymphoma with 131I-labeled anti-Thy 1.1 monoclonal antibody.

Monoclonal antibodies against the Thy 1.1 differentiation antigen are ineffective in the treatment of transplanted AKR T-cell lymphoma once a palpable tumor nodule is present, due to the inability of the host to eliminate antibody-coated tumor cells. To overcome this limitation, we have evaluated the use of 131I-labeled anti-Thy 1.1 antibodies for the therapy of established AKR/J SL2 lymphoma (Thy 1.1+) nodules growing in congeneic AKR/Cu mice (Thy 1.2+). In these experiments, 131I-anti-Thy 1.1 antibody specifically localized to a s.c. tumor with a mean of 6.5% of the infused dose per g of tumor at 24 h after infusion. The proportion of infused anti-Thy 1.1 antibody localizing to tumor was constant following antibody doses of up to 400 micrograms/animal. Antibody iodinated with up to 2 atoms of iodine per antibody of molecule maintained binding activity and localization to tumor equivalent to antibody labeled with less iodine. The concentrations of 131I-anti-Thy 1.1 in tumor would result in delivery of a mean of 1600 cGy to tumor following infusion of 500 muCi of 131I-labeled anti-Thy 1.1 antibody. In comparison, 500 muCi 131I-labeled irrelevant antibody would deliver a mean of 380 cGy to tumor. Treatment of animals with palpable tumor nodules with 500 muCi 131I-anti-Thy 1.1 led to regression of the tumor nodule in 44% of animals, significantly prolonged survival, and cured two of five of the animals treated prior to the development of metastatic disease. In contrast, unlabeled anti-Thy 1.1 led to tumor response in 6% of animals, and up to 1000 muCi 131I-labeled irrelevant antibody had no effect on tumor growth. Therapy was limited by the emergence of variant tumor cells lacking the target antigen and by bone marrow toxicity following 131I-labeled antibody doses of greater than or equal to 1000 muCi/animal. These studies demonstrate that 131I-labeled monoclonal antibodies can have a significant antitumor effect in a situation where unmodified antibody is ineffective.

Experimental radioimmunotherapy of murine lymphoma with 131I-labeled anti-T-cell antibodies.

We have shown previously that 131I-labeled antibodies against the Thy-1.1 differentiation antigen can cure AKR/Cum (Thy-1.2+) mice bearing AKR/J (Thy-1.1+) SL2 T-cell lymphoma. In the present study we have extended these studies to the therapy of SL2 lymphoma in AKR/J mice, where 131I-anti-labeled Thy-1.1 antibodies react with both tumor and normal T-lymphocytes. A single 25-micrograms bolus of 131I-labeled anti-Thy-1.1 antibody was rapidly cleared from serum by binding to spleen cells (t1/2 less than 3 h) and only low concentrations (less than 2% injected dose/g) were present in tumor 24 h after infusion. Doses of 0.5-5.0 mg antibody saturated cells in the spleen but only slightly increased the proportion of antibody in tumor. In contrast, pretreatment of mice with 1.0 mg of unlabeled anti-Thy-1.1 antibody 24 h prior to 131I-labeled antibody resulted in a tumor concentration of 9.7% injected dose/g 24 h after infusion of the radiolabeled antibody. With this latter regimen, biodistribution approximated that seen in AKR/Cum mice, and infusion of 1,000 mu Ci would result in delivery of 16 Gy to tumor. Therapy of AKR/J mice bearing established s.c. lymphoma nodules with 1,500 mu Ci of 131I-anti-Thy-1.1 antibody given in this latter regimen resulted in complete regression of the nodule in 70% of animals and had a greater antitumor effect (27% complete regression, P less than 0.001) than 750 mu Ci of 131I-labeled irrelevant antibody, a dose that would deliver equivalent radiation to normal organs (liver, kidney, and lung). The anti-Thy-1.1 antibody had only a slightly greater antitumor effect than an equivalent mu Ci dose (1,500 mu Ci) of 131I-labeled control antibody (42% complete regression, P = 0.12). Both antibodies were marrow toxic and all animals treated with 1,500 mu Ci died of marrow aplasia. These studies suggest that radiolabeled antibodies against differentiation antigens may be useful for therapy in spite of binding to normal cell populations but curative therapy may require infusion of unirradiated bone marrow.

Biodistribution and dosimetry following infusion of antibodies labeled with large amounts of 131I.

Dosimetry and treatment planning for therapeutic infusions of radiolabeled antibodies are usually performed by extrapolation from the biodistribution of trace-labeled antibody. This extrapolation assumes that the biodistribution of high specific activity antibody will be similar to that seen with trace-labeled antibody. However, high doses of radiation result in rapid depletion of lymphoid and hematopoietic cells in lymph nodes, spleen, and marrow with replacement by blood and plasma. If radiolabeled antibody is cleared slowly from blood, this replacement may result in increased radionuclide concentrations in these tissues following infusions of antibody labeled with large amounts of radionuclide. To examine the influence of deposited radiation on the biodistribution of radiolabeled antibody, we treated mice with a constant amount of antibody that was labeled with varying amounts of 131I. Survival was determined in normal specific pathogen-free AKR/Cum mice (Thy1.2+) after infusion of anti-Thy1.1 antibody labeled with 10 to 6500 muCi of 131I, to determine an appropriate range of 131I doses for further study. The dose producing 50% lethality within 30 days following infusion of 131I-labeled antibody was 530 muCi 131I. Biodistribution, bone marrow histology, and dosimetry were subsequently determined after infusion of 500 micrograms of antibody labeled with 10, 250, 500, or 3500 muCi 131I. The amount of 131I did not influence uptake or retention of antibody in blood, liver, lung, or kidney. In contrast, infusion of antibody labeled with 250 to 3500 muCi of 131I led to a dose-related increase in the concentration of 131I in marrow, spleen, lymph node, and thymus. For example, at 96 h after infusion of antibody labeled with 500 or 3500 muCi 131I, concentrations in marrow were 3- to 4-fold higher than after infusion of trace-labeled antibody. The increase in marrow 131I concentrations was associated with depletion of cells and hemorrhage within the marrow space. As a result, estimated mean absorbed doses to marrow, lymph node, spleen, and thymus were 1.2 to 3.1 times higher than would have been predicted from the biodistribution of trace-labeled antibody. These results suggest that the biodistribution of trace-labeled antibody should be an accurate predictor of the behavior of high specific activity antibody in blood and solid organs such as liver and kidney. In contrast, radiation from antibody labeled with large amounts of radionuclide can result in an alteration of the concentration of radiolabeled antibody in rapidly responding tissues such as marrow.(ABSTRACT TRUNCATED AT 400 WORDS)

Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation.

PURPOSE: Hepatic venoocclusive disease (VOD) is a common complication of cytoreductive therapy for marrow transplantation. Only 25% of patients who develop VOD have severe disease. We tested the hypothesis that early clinical signs of VOD would predict which patients would recover and which would die. PATIENTS AND METHODS: We evaluated 355 consecutive patients who had transplants between August 6, 1987 and July 21, 1988 for occurrence of VOD and whether it was reversible within 100 days of transplant. Total serum bilirubin and weight gain from day -7 through day +16 posttransplant were compared among patients with no, severe, or nonsevere VOD. Logistic regression models were developed to estimate probabilities of severe VOD at each of six time intervals. The accuracy of these models was tested by applying them to 392 consecutive patients who underwent transplantation between July 22, 1988 and July 20, 1989. RESULTS: As early as day -1, bilirubin and weight gain were significantly different between patients whose VOD proved to be severe and patients with reversible VOD or no disease. Regression models were used to generate coefficients (beta 0, beta 1, beta 2) for the equation P = 1/(1 + e-z), where P is the probability of severe VOD and z = beta 0 + beta 1 (In total serum bilirubin [mg/dL]) + beta 2 (percent weight gain). Application of this equation to the next 392 patients allowed us to calculate sensitivity, specificity, and positive predictive value for a range of probabilities. CONCLUSION: The course of VOD after cytoreductive therapy can be predicted by knowing the serum bilirubin and weight gained within 1 to 2 weeks of transplantation. Probability estimates derived from patient data are highly specific and moderately sensitive. Such probability estimates may be useful when considering potentially risky interventions to treat VOD, such as recombinant human tissue plasminogen activator.

Occult B cell malignancies can be detected by three-color flow cytometry in patients with cytopenias.

Patients with unexplained cytopenias often present a diagnostic dilemma with minimal morphologic or cytogenetic changes to identify the underlying disease process. We have used multidimensional flow cytometry in a study of patients with cytopenias and found that this technology established, changed, or refined the diagnosis in 17/121 patients. Using the flow cytometric technique of CD45 and right angle light scatter (SSC) gating with two additional markers in a three-color analysis, eight of 121 patients were found to have hairy cell leukemia (HCL), in the absence of definitive morphologic findings of HCL. Two additional patients were found to have non-Hodgkin's lymphoma (NHL). Myeloid abnormalities, myelodysplasia (MDS) or acute leukemia was detected in seven of 56 patients with unexplained pancytopenia. Six of 65 patients identified with cytopenias resulting from lymphoid neoplasms had been referred for bone marrow transplantation (BMT) with a presumptive diagnosis of MDS, with subsequent deferral of BMT upon correct diagnosis. The screening technique is incorporated into an extensive immunophenotyping scheme to identify hematopoietic abnormalities using multidimensional flow cytometry (MDF). HCL cells (detected as low as 1.3%) reside in the same position as normal monocytes in the CD45 and SSC plots but could be distinguished from monocytes based on the expression of HLA-DR without CD11b, and expression of CD19. Further phenotyping of the abnormal population confirmed immunoglobulin light chain restriction, CD11c, and CD25 expression. Non-Hodgkin's lymphoma was detected as aberrant mature lymphocytes expressing B lymphoid markers, CD5 and light chain restriction. Myeloid abnormalities were identified in the myeloblast or maturing myeloid cell fractions. The flow cytometric scheme described can be used in primary diagnosis. The technique is definitive, sensitive, and stresses the importance of distinguishing lymphoid from myeloid etiology of cytopenias.

A comparison of small-area hospitalisation rates, estimated morbidity and hospital access.

Published data on hospitalisation rates tend to reveal marked spatial variations within a city or region. Such variations may simply reflect corresponding variations in need at the small-area level. However, they might also be a consequence of poorer accessibility to medical facilities for certain communities within the region. To help answer this question it is important to compare these variable hospitalisation rates with small-area estimates of need. This paper first maps hospitalisation rates at the small-area level across the region of Yorkshire in the UK to show the spatial variations present. Then the Health Survey of England is used to explore the characteristics of persons with heart disease, using chi-square and logistic regression analysis. Using the most significant variables from this analysis the authors build a spatial microsimulation model of morbidity for heart disease for the Yorkshire region. We then compare these estimates of need with the patterns of hospitalisation rates seen across the region.

Audiological evaluation of nonalcoholic, drug-free posttraumatic stress disorder patients.

Auditory functions of 32 Israeli soldiers with posttraumatic stress disorder (PTSD) were evaluated and compared with those of 32 matched controls without PTSD. The evaluation included peripheral auditory functions, tolerance to noise, and central auditory informational functions. Tolerance of intense auditory stimuli by PTSD patients was similar to that of controls. Significant differences were found between left and right ear central auditory functions in a subgroup of 13 PTSD subjects, but neither in other PTSD patients nor in controls. These findings are discussed in the light of previous research concerning abnormal responses to auditory stimulus in PTSD, hemispheric disconnection, alexithymia, and psychosomatic disorders.

The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients.

We reviewed 355 autopsies performed between 1990 and 1994 at a major marrow transplant center to determine whether fluconazole prophylaxis prevented visceral fungal infection. Fluconazole prophylaxis was defined by a minimum of 5 prophylactic doses. Fungal infection (any site) was found in 40% of patients transplanted and autopsied at the center. Overall, the proportion of autopsies with any fungal infection was not different for those patients receiving no fluconazole prophylaxis versus those with prophylactic fluconazole. With fluconazole prophylaxis, candidal infections were less frequent, decreasing from 27% to 8%, while Aspergillus infections were more frequent, increasing from 18% to 29%. No increase in deaths related to non-albicans Candida infections was seen. Of the 329 patients with livers examined, hepatic infection caused by Candida species was significantly less common in patients who had received fluconazole. Fungal liver infection was found in 31 patients (9%), 16% of those who were not treated with fluconazole and 3% of those who were treated with fluconazole. Since patients with candidal infections died earlier after marrow transplant than patients with mold infections, we speculate that a longer length of survival may dispose toward acquisition of mold infections. Fluconazole prophylaxis in this cohort of marrow transplant patients undergoing autopsy resulted in a significant reduction in infection caused by Candida species and an increase in mold infections.

Fluctuations in plasma dopamine level impair memory in Parkinson's disease.

We found a causal relationship between variation in plasma dopamine level and memory impairment in Parkinson's disease. If the level of dopamine was changed between the time of original learning and a later time of attempted memory retrieval, memory performance was impaired when compared with a maintenance of similar dopamine levels on both occasions. The absolute level of dopamine did not influence memory performance. Side-effects of levodopa-carbidopa therapy include variation in dopamine level, parkinsonian symptoms, and possibly "state-dependent" impairment of memory.

Dose-dependent memory impairment in Parkinson's disease.

Variation in plasma dopamine level between the time of original learning and subsequent memory retrieval causes a state-dependent memory impairment in Parkinson's disease. The occurrence of this phenomenon is not related to either progression of disease or duration of therapy, but is more likely to occur with high-dosage levels of levodopa-carbidopa.

Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients.

This study of chronic graft-versus-host disease (GVHD) describes the clinical, pathologic and laboratory features, and the causes of morbidity and mortality in 20 patients who received allogeneic marrow transplants from HLA identical sibling donors. Chronic GVHD is a pleiotrophic syndrome with variability in the time of onset, organ systems involved and rate of progression. The clinical-pathologic features resemble an overlap of several collagen vascular diseases with frequent involvement of the skin, liver, eyes, mouth, upper respiratory tract, esophagus and less frequent involvement of the serosal surfaces, lower gastrointestinal tract and skeletal muscles. Major causes of morbidity are scleroderma with contractures and ulceration, dry eyes and mouth, pulmonary insufficiency and wasting. Chronic GVHD has features of immune dysregulation with elevated levels of eosinophils, circulating autoantibodies, hypergammaglobulinemia and plasmacytosis of viscera and lymph nodes. In this study, three patients had limited chronic GVHD with relatively favorable prognosis characterized by localized skin involvement and/or hepatic disease without chronic aggressive histology. Most patients, however, had extensive disease with a progressive course. Survival was largely determined by the presence or absence of serious recurrent bacterial infections. The over-all severity of disease was best assessed by using the Karnofsky performance rating.

Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size, and fractionation interval on acute and delayed toxicity.

Dogs were given single dose or fractionated total body irradiation (TBI) and autologous marrow grafts to prevent death from myelosuppression. Acute and delayed non-marrow toxicities were compared. Fifty-six dogs were given single dose TBI at 2.1 (n = 13), 5 (n = 12), 10 (n = 15), or 20 (n = 16) cGy/min. Acute radiation toxicity and mortality was related to the exposure rate; radiation doses resulting in 50% mortality at 7 days (LD 50/7) at 2.1, 5, 10 and 20 cGy/min were 1,692, 1,499, 1,261, and 1,056 cGy respectively. Fifty-three dogs were given fractionated TBI, 200 cGy three times a day with 6-hour intervals at 2.1 (n = 13), 5 (n = 9), 10 (n = 13), or 20 (n = 18) cGy/min. The LD 50/7 at the four exposure rates were 1,628, 1,470, 1,184, and 1,320 respectively. Thus, for exposure rates of 2.1, 5, and 10 cGy/min, the tolerated doses were comparable for single dose and fractionated TBI. At 20 cGy/min dose fractionation appeared to offer some advantage, although this fractionation effect in part may have been due to random variation with small numbers of dog treated. Following recovery from the immediate TBI-related toxicity, eight dogs given single dose and four dogs given fractionated TBI died, generally from infections, 8-30 days following transplantation. There was a striking difference in regards to long-term survival dependent upon the TBI regimen. Among dogs given greater than or equal to 1,000 cGy of TBI and alive 30 days after transplant only 1 of 18 given single dose TBI became a long-term survivor compared to 19 of 22 given fractionated TBI. Causes of death included pancreatic fibrosis, malnutrition, hepatic failure, and a generalized wasting syndrome. All 5 dogs given a single dose of 800 cGy (at 20 cGy/min) became long-term survivors. Fourteen dogs were given increments of 150 cGy at 7 cGy/min every 3 hours for total doses of 1,500-2,400 cGy. The LD 50/7 was approximately 1,900 cGy. All 6 dogs alive at 30 days became healthy long-term survivors. Four dogs were given increments of 600 cGy at 2.1 cGy/min every 48 hours for a total dose of 1,800 cGy. All 4 dogs became long-term survivors. In conclusion, exposure rate and total dose are the most important parameters for acute toxicity associated with TBI. The effect of dose fractionation is minimal at low exposure rates and appears to be dependent also upon increment size and fractionation interval.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose rate-dependent sparing of the gastrointestinal tract by fractionated total body irradiation in dogs given marrow autografts.

PURPOSE: We compared gastrointestinal toxicity of single vs. fractionated total body irradiation (TBI) administered at dose rates ranging from 0.021 to 0.75 Gy/min in a canine model of marrow transplantation. METHODS AND MATERIALS: Dogs were given otherwise marrow-lethal single or fractionated TBI from dual 60Co sources at total doses ranging from 8-18 Gy and delivered at dose rates of 0.021, 0.05, 0.10, 0.20, 0.40, and 0.75 Gy/min, respectively. They were protected from marrow death by infusion of previously stored autologous marrow cells and they were given intensive supportive care posttransplant. The study endpoint was 10-day mortality from gastrointestinal toxicity. Logistic regression analyses were used to jointly evaluate the effects of dose rate, total dose, and delivery regimen on toxicity. RESULTS AND CONCLUSION: With increasing dose rates, mortality increased for either mode of delivery of TBI. With dose rates through 0.10 Gy/min, mortality among dogs given single vs. fractionated TBI appeared comparable. Beginning at 0.20 Gy/min, fractionation appeared protective for the gastrointestinal tract. Results in dogs given TBI at 0.40 and 0.75 Gy/min, respectively, were comparable, and dose fractionation permitted the administration of considerably higher total doses of TBI than were possible after single doses, an increment that was on the order of 4.00 Gy. The data indicate that the impact of fractionating the total dose at high dose rates differs from the effect of fractionation at low dose rates.

Marrow toxicity of fractionated vs. single dose total body irradiation is identical in a canine model.

PURPOSE: We explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing 60Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. RESULTS: We found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionated total body irradiation (p = .18). One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation (p > .20). With granulocyte colony stimulating factor administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with granulocyte colony stimulating factor after 400 cGy single dose total body irradiation, a study of granulocyte colony stimulating factor after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with granulocyte colony stimulating factor administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. CONCLUSION: Within the limitations of the experimental design, we conclude that single-dose and fractionated total body irradiation have comparable marrow toxicity in dogs.

Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy.

Evaluation of the diagnostic utility of the rectal biopsy in graft-versus-host disease (GVHD), using the crypt abscess as a major diagnostic criterion, was based on 52 patients who had received marrow allografts for leukemia or aplastic anemia. Thirty-six of these patients had acute GVHD by skin biopsy criteria. These 36 patients demonstrated a strong association of the rectal crypt abscess with severity of clinical GVHD. High stool volume also correlated strongly with the crypt abscess. Patients without clear evidence of GVHD usually had normal rectal histology. Serial studies showed a good correlation of rectal biopsy results with the clinical course of acute GVHD. Patients with chronic GVHD had rectal mucosal damage only during the acute phase. Rectal ileal and cecal disease accurately. The rectal biopsy is a useful adjunct to serial skin biopsies in the diagnosis of GVHD in man.

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation.

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.

The fine structure of human rectal epithelium in acute graft-versus-host disease.

We compared the fine structure of the biopsied rectal mucosa of seven allogeneic bone marrow transplant recipients who had gastrointestinal graft-versus-host disease (GVHD) with that of four recipients without GVHD. In GVHD, lymphocytes formed the predominant cellular infiltrate. Lymphocytes indented the cytoplasmic membranes of enterocytes by point contact, extended broad pseudopods to the nuclear membranes of the enterocytes, and surrounded desmosomes. The membranes of target cells were never breached, however. We hypothesize that these lymphocyte-to-epithelial-cell contacts represent the recognition phase of alloimmune T-lymphocyte cytolysis. Damage to the enterocytes resulted in both coagulative necrosis and "apoptosis" (the development of membrane-bound cell fragments--"apoptotic bodies"). Epithelial injury and lymphocytic infiltration predominated in the bases of the crypts in mild GVHD and extended to the surface epithelium in severe GVHD. Chemoradiotherapy-induced injury, present early post-transplant, was diffuse and severe but transient. In GVHD, damage to the enterocytes, necrosis, and intercellular edema extended beyond the time of resolution of chemoradiotherapy-induced injuries. Patients without GVHD, studied after resolution of chemoradiation injury, had rectal epithelium with little or no injury and no evidence of either increased numbers of lymphocytes or of the intimate lymphocyte-to-epithelial-cell contacts described in those with GVHD.