Summary
Immunohistological study of lung biopsies from four palients with farmer's lung revealed histological evidence of vasculilis along with deposits of immunoglobulins and C3 in and around the affected vessels in the biopsies from two palients. Both these patients were exposed to mouldy hay antigens shortly before biopsy. Both these patients also had considerable numbers of eosinophils in their lung lesions. Immune‐complex mediated vasculitis is probably an early event in the pathogenesis of farmer's lung and might not be detectable in the absence of recent exposure to relevant antigens. The presence of large numbers of eosinophits in these lesions suggests a type I reaction acting as the trigger for a type 3 reaction.
The incidence of leukemia is higher among those closely exposed than among those more remote from the hypocenter. This increase was first manifest approximately three years following exposure. It apparently reached its peak between the years 1950 and 1952. Thereafter, the incidence has been diminishing, but 13 years after exposure it is still higher than would be expected in the general population. The type of leukemia most increased in incidence is the chronic granulocytic variety. No apparent difference in the natural history of the specific types of leukemia in exposed and nonexposed Japanese has been observed. Preliminary analyses of the data show a linear relation between dose of radiation and incidence of leukemia above 50 to 100 rad. Below this dose, the shape of the curve is not certain.
In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX, 1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX gamma-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX gamma-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugate was formed when the MTX gamma-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoroacetaldehyde, which were reacted with nucleophilic centers, presumably epsilon-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX gamma-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhat more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.
Methotrexate (MTX) was first conjugated to antibovine serum albumin IgG (antiBSA) or its F(ab)2 fragment to define conditions for retention of drug and antibody activity. With identical drug: protein molar ratios, incorporation in the F(ab)2 fragment was lower than in intact antiBSA, an observation consistent with analysis of the number of lysine residues (22 in F(ab)2 compared to 40 in antiBSA). In either case, up to approximately 10 mol MTX could be incorporated per mol protein, with recovery of 70% of the protein. At an incorporation ratio of 6 mol MTX per mol protein, MTX-antiBSA retained 100% of antibody activity and MTX-F(ab)2-antiBSA retained 75%. MTX-antiBSA and MTX-F(ab)2antiBSA were equally potent in vitro inhibitors of dihydrofolate reductase. Conjugates prepared from antiEL4 IgG (AELG) and from F(ab)2AELG significantly increased survival in EL4 lymphoma-bearing mice compared with mice receiving equal amounts (5 mg MTX/kg) of free MTX, MTX linked to the F(ab)2 fragment of normal rabbit IgG, or a simple mixture of MTX and F(ab)2AELG. MTX-AELG at this dose level produced longer survival than MTX-F(ab)2AELG (0.005 less than P less than 0.01).
A surface‐localizing heterologous antibody against the mouse Ehrlich ascites carcinoma could be bound to chlorambucil without causing the loss of alkylating activity of chlorambucil or interfering with the reactivity of the antibody with tumor cells. Chlorambucil, when bound to the antibody, was a much more effective tumor inhibitor, both in vitro and in vivo, than chlorambucil or the antibody alone.
Injections of appropriate numbers of irradiated tumor cells produced antibodies against tumor cell-surface antigen(s) in both syngeneic tumor models studied: the early transplant generations of the spontaneous L2 lymphoma in AKR/J mice and the chemically induced EL 4 lymphoma in C57BL/6J mice. No antibody was detected in normal or nonimmunized tumor-bearing mice. Tumor inhibitory or enhancing activity was not demonstrated by these antibodies. Immunoprophylaxis or cell-mediated immunity against the L2 lymphoma was not observed after injections of irradiated L2 cells and/or BCG into AKR mice. However, injections of irradiated EL 4 cells alone were effective in immunoprophylaxis against as many as 10(6) EL 4 cells and in immunotherapy against 10(2) EL 4 cells per mouse. The addition of BCG injections made immunotherapy with irradiated EL 4 cells effective against a load of 10(4) EL 4 cells/mouse, though BCG alone was not effective for immunoprophylaxis against EL 4 cells. Resistance to EL 4 could be transferred with viable syngeneic peritoneal or nucleated spleen cells. In both tumor models, an ongoing delayed hypersensitivity reaction to BCG alone apparently did not inhibit bystander tumor cells even when tumor cells were mixed before inoculation with viable BCG. In neither tumor model were concanavalin A-coated tumor cells more potent for immunoprophylaxis than were irradiated tumor cells alone.
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