Dharmendra P.S. Sengar

The effect of immunosuppressive chemotherapy on immune function in patients with malignant disease

This paper reviews studies previously conducted on the effect of anticancer drugs on immune function in man. It provides new data reporting on the effect of short intensive courses of cytotoxic drug therapy on B‐lymphocyte and T‐lymphocyte number in cancer patients. Both types of lymphocyte were found in this investigation to be equally sensitive to cytotoxic drugs. The degree of absolute cell number reduction and rate of recovery were similar for T‐lymphocytes and B‐lymphocytes. Other workers have demonstrated, however, that with prolonged administration of cytotoxic drugs B‐lymphocyte number and function are more adversely affected than are T‐lymphocyte number and function. Immune function which had been suppressed by continuous programs of chemotherapy for periods of up to 2–3 years will, in certain groups of patients, recover to normal or almost normal levels of function. Short courses of combination drug chemotherapy may be followed by “rebound‐overshoot” recovery of immune function. This has been associated with a more favorable clinical course than in situations where it does not occur. Chemotherapy and chemoimmunotherapy programs in clinical oncology ought ideally to be initially evaluated for the effect that they have on immune function. This will permit the development of drug dose and time schedules which allow for recovery of immune function and may possibly lead to augmented antitumor responses.

Early-onset autoimmune hepatitis is associated with a C4A gene deletion

BACKGROUND Autoimmune hepatitis is an immunologically mediated disorder with some similarities to systemic lupus erythematosus, including an association with HLA-A1, B8, DR3. This haplotype includes a C4A, 21-OHA gene deletion. Low serum levels of complement and C4 null alleles have been reported in autoimmune hepatitis, but studies have been at the protein level only. METHODS Twenty-four white patients with autoimmune hepatitis were studied by Southern blots using a C4A gene complementary DNA probe. HLA A, B, and C typing was determined using standard microcytotoxicity assays, and DR and DQ specificities were determined by restriction fragment length polymorphism analysis. RESULTS Thirteen of 24 patients had the C4A gene deletion compared with 12 of 90 controls. HLA-A1 and B8 were increased in patients with autoimmune hepatitis, as were HLA-DR3 (DR17), Dw24, DQ2. Patients with a C4A gene deletion presented at a younger age than those without the deletion and had significantly lower serum C3 and C4 levels. The C4A gene deletion was associated with HLA-A1, B8, DR3 in all but 1 patient who was HLA-DR3 negative. CONCLUSIONS A C4A gene deletion is found in patients with autoimmune hepatitis, especially those presenting at a young age. This complement gene deletion may be an important factor in the development of this disease.

In vitro Cellular Immunity and in vivo Delayed Hypersensitivity in Uremic Patients Maintained on Hemodialysis

Uremic patients on hemodialysis for periods in excess of 1 year have a significantly better survival rate for their renal allografts than do similar patients hemodialyzed for less than 1 year. Lymphoc

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis

BACKGROUND Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögrens syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögrens syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögrens syndrome), oligoclonal rearrangement in the other. INTERPRETATION Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.

HLA Antigens in Bronchogenic Carcinoma

A decrease in the frequency of HLA-A2 was noticed in 37 bronchogenic carcinoma patients studied. HLA-B8 was found to be increased in the prolonged survivors of bronchogenic carcinoma.

Acute promyelocytic leukemia associated with a paraprotein that reacts with leukemic cells

A 29‐year‐old woman developed acute promyelocytic leukemia during pregnancy. At diagnosis, immediately postpartum, she was found to have IgG kappa immunoglobulin on the surface of the leukemic cells as well as a monoclonal protein of IgG kappa specificity in her serum. These resolved with chemotherapy which induced a complete remission. Immunoglobulin gene rearrangement was not found in the leukemic cells, thus indicating that the blasts were not secreting the monoclonal protein. The authors believe that the patient had an autoantibody directed at myeloid cells which was amplified by the development of the leukemic process.

Correlation in Hemodialysis Patients and Renal Allograft Recipients between Percent T Lymphocytes in Peripheral Blood and in vitro Lymphocyte Responses to Nonspecific Mitogenic Agents

Both hemodialysis and renal allograft recipients have a significantly reduced number of total T lymphocytes per microliter of blood. Simultaneous in vitro lymphocyte responsiveness to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) revealed in the normal subjects, a positive correlation (r = +0.427) between percent T lymphocytes and PHA and a negative correlation (r = -0.525) between percent T lymphocytes and PWM. Such trends were not observed in the hemodialysis patients and transplant recipients. Thus, the enumeration of lymphocytes as T cells appears to provide no clear indication of their functional capacity to respond to mitogenic stimulation in these two categories of patients.

Relationship of Blood Transfusions to Appearance of Mixed Leukocyte Culture Blocking Factor Activity in Plasma of Uraemic Patients and Renal Allograft Recipients

Abstract. Plasma samples from haemodialysis patients, renal allograft recipients and haemophiliacs were studied for the presence of mixed leukocyte culture blocking factor activity (BFA). A history of blood transfusions received within the preceding 6 months of testing was significantly and directly correlated with the appearance and persistence of BFA in the plasma of haemodialysis patients. This association was not found in renal allograft recipients. The development of BFA was found to be associated with formation of lymphocytotoxins but not haemagglutinins. The authors have also demonstrated that BFA resides in the IgG fractions of serum samples obtained from both chronic uraemics undergoing haemodialysis and patients bearing renal allografts. BFA may play a minor role in the acceptance of human renal allografts.

Lymphocyte Transformation in Human Plasma without Addition of Synthetic Medium

The in vitro response of lymphocytes obtained from normal subjects, uraemic patients on haemodialysis and diabetic patients was studied using cultures containing either medium plus plasma (medium cultures) or plasma alone (plasma cultures). The study demonstrated that plasma alone can adequately support lymphocyte transformation induced by nonspecific mitogens (PHA and PWM) and allogeneic lymphocytes in mixed lymphocyte culture (MLC) reaction. This investigation further confirms our previously reported findings that uraemic patients undergoing haemodialysis have a normal lymphocyte response in MLC and to PHA and PWM. Plasma cultures give results similar to conventional medium cultures in subjects where lymphocyte transformation is normal. The lymphocyte hyporactivity observed in diabetics is, however, better shown in the plasma cultures. The suppressed response of the diabetic patients lymphocytes to PHA and PWM both in the presence of autologous and normal AB plasma suggests intrinsic lymphocyte dysfunction as the explanation for impaired immune function. Plasma cultures may provide a better in vitro system for the evaluation of immune function in certain groups of patients where it is desirable to distinguish between intrinsic abnormalities of lymphocyte function and the effect of humoral immunosuppressive factors.

Beneficial Effect of Hemodialysis on Renal Allograft Survival

The effect of the length of hemodialysis on the outcome of renal transplant was evaluated in 43 recipients of renal allograft. 22 out of 23 patients (95.7%) dialyzed for longer than one year had an excellent renal function at one year, while only 10 out of 20 patients (50%) dialyzed for less than one year had good renal function at one year. Only one kidney (4.3%) was lost due to rejection in the first group, while 10 kidneys (50%) failed to function because of severe rejection in the second group. The length of hemodialysis appears to have a beneficial effect on graft survival, but the mechanism by which it exerts this effect is not clear.