ALLOGENEIC THYMUS GRAFTS AND THE RESTORATION OF IMMUNE FUNCTION IN IRRADIATED THYMECTOMIZED MICE

Irradiated and thymectomized CBA mice are markedly depressed in several immunological parameters (skin homograft rejection, graft-vs.-host activity and hemolytic plaque-forming cells of the spleen, hemolysin and hemagglutinin formation, and peripheral lymphocyte counts). In the present experiments the ability of homografts of neonatal thymus placed beneath the kidney capsule to restore immunological capacity of such animals was studied. Thymus homografts which share the same H-2 locus with the CBA mouse were permanently tolerated and immunological restoration was complete. Skin from the thymus donor was specifically retained, but third party skin with even minor (non-H-2) incompatibility was normally rejected and hemolytic plaque-forming cells of the spleen were restored. Thymus homografts which differ at the H-2 locus were promptly rejected and led to accelerated rejection of skin subsequently grafted from the thymus donor. With such H-2 incompatible thymus grafts, third party skin with minor histo-incompatibility was retained while there was slight to moderate restoration of rejection of skin with major (H-2) incompatibility. Graft-vs.-host activity was restored, but there was no return of plaque-forming spleen cells, hemolysins, hemagglutinins, or peripheral lymphocyte counts. In view of the cross-reactivity at the H-2 locus in CBA mice between thymus and third party skin donors, it was felt that restoration of skin rejection and graft-vs.-host activity could be adequately explained on the basis of immunization by the thymus graft and did not require the postulation of true immune restoration or a thymus hormone

THE THYMUS AND RECOVERY FROM CYCLOPHOSPHAMIDE-INDUCED TOLERANCE TO SHEEP ERYTHROCYTES

Recovery from specific immunological tolerance to sheep erythrocytes induced with the drug cyclophosphamide was studied with the hemolytic plaque technique of Jerne. The base line plaque (19S antibody-forming cell of the unstimulated spleen) and the proliferative response to antigen, both of which had disappeared during tolerance induction, returned with the recovery of specific immunological reactivity. When cyclophosphamide is injected without sheep cells there is temporary immunological unreactivity and lymphoid depletion of the spleen, but specific tolerance is not induced. Recovery is largely complete at the end of 2 wk and does not require the participation of the thymus. When cyclophosphamide is injected together with sheep cells, 18 days after drug injection, tolerance is still complete. In nonthymectomized mice there is rapid recovery during the next 10 wk, followed by much slower restoration over the remaining 20–30 wk of observation. The entire recovery process evidently takes 40–50 wk. In thymectomized CBA mice only minimal recovery takes place in the first 10 wk and no further restoration occurs thereafter. Thymectomy performed 18 days after tolerance is induced, when tolerance is complete, is equally effective in preventing this recovery

AN ELECTRON MICROSCOPE STUDY OF LYMPHATIC TISSUE IN RUNT DISEASE

The thymus, spleen, and lymph nodes were studied in runt disease induced by a graft of intravenously injected homologous splenic cells into newborn rats and mice. Adult Long-Evans cells (70 x 106) were injected into Sprague-Dawley rats. Adult DBA cells (7 x 106) were injected into C57BL/6 mice. Runted rats were sacrificed at 14 to 28 days of age; mice at 10 to 20 days. The thymic cortex is depleted of small lymphocytes. Those remaining are severely damaged and phagocytized. Evidence of damage includes swelling of mitochondria, myelin figure formation, margination of chromatin, and sharp angulation in nuclear contour. Large numbers of macrophages are present. Epithelial-reticular cells which envelop small cortical blood vessels are often retracted, with the result that the most peripheral layer in the thymic-blood barrier suffers abnormally large gaps. Lymphocytes of the periarterial lymphatic sheaths of spleen and of the cortex of lymph nodes are reduced in number and damaged. Vast numbers of plasma cells and many lymphocytes are evident throughout lymph nodes, in the periarterial lymphatic sheaths, and in the marginal zone and red pulp of the spleen. Plasma cells are of different sizes, the larger having dilated sacs of endoplasmic reticulum. Lymphocytes are small to medium in size. They contain, in varying quantity, ribosomes and smooth membrane-bounded cytoplasmic vesicles approximately 350 to 500 A in diameter. Most plasma cells and lymphocytes are damaged and many of these are phagocytized. Many lymphocytes in lymph nodes, however, show no evidence of damage. Reticular cells and other fixed cells of the connective tissues seldom appear affected. Thus, the major cell types reacting in runt disease are lymphocytes, plasma cells, and histiocytes or macrophages. It appears, therefore, that both the delayed and immediate types of sensitivity play a part in this disease

THE THYMUS AND RECOVERY OF THE SHEEP ERYTHROCYTE RESPONSE IN IRRADIATED MICE

The role of the thymus in the recovery of the sheep erythrocyte response after lethal irradiation has been studied in adult CBA mice with the hemolytic plaque technique of Jerne. This immunological parameter is markedly thymus-dependent. 10 wk after irradiation and after antigenic challenge the thymectomized animal has only one-twentieth to one-fortieth the number of plaque-forming cells as does the irradiated animal with intact thymus. The thymus continues to function into the 7th and 8th month of life in this strain. Unlike the drug-tolerant animal, the incompetent irradiated thymectomized mouse retains base line plaques (plaques without antigenic stimulation). Thymectomy 18 days after irradiation is as effective as prior thymectomy in preventing recovery of the sheep cell response. Thymectomized animals receiving grafts of isogenic neonatal thymus (placed beneath the kidney capsule) 1 day, 1 wk, or 2 wk after irradiation are somewhat more responsive at 10 wk than intact animals. Grafts in place for 1 or 2 wk after irradiation and then removed result in one-fifth the recovery of grafts in place the entire time, while only slight restoration is obtained from grafts in place for the final 3 wk of the experiment. The results indicate that the thymus is not required for the 18 days after irradiation, that a period of at least 3 wk residence is required for complete restoration, and that the thymus itself is somewhat radiation-sensitive. Allogeneic thymus grafts failed to restore the hemolysin response of irradiated thymectomized animals

THE CONTRASTING EFFECTS OF CYCLOPHOSPHAMIDE AND RADIATION ON THE IMMUNE RESPONSES OF THE MOUSE

The immunosuppressant cyclophosphamide easily induces specific immunological tolerance in CBA mice, but is unable to produce an immunological defect in adult thymectomized animals. In contrast, lethal (and sublethal) irradiation does not induce tolerance but readily brings out the deficit of thymectomy. Furthermore, bone marrow cells which protect lethally irradiated animals do not prevent drug deaths. This sharp dichotomy indicates that the drug and radiation influence the lymphoid system by different mechanisms. It seems likely from the work of others that cyclophosphamide action is markedly dependent on rapid cell proliferation, while radiation is not. From this it follows that the cell which must be depleted to expose the immune defect of the thymectomized animal is a nonproliferating lymphoid element with the slow mitotic rate of the marrow stem cell

Clinical outcome of breast cancer occurring after treatment for Hodgkin's lymphoma: case-control analysis

<p>Abstract</p> <p>Background</p> <p>To evaluate diagnosis, management and outcome of breast cancer (BC) occurring after irradiation for Hodgkin's lymphoma (HL).</p> <p>Methods</p> <p>39 cases of BC in 28 HL survivors were retrospectively reviewed. 21 patients were included in a case-control analysis.</p> <p>Results</p> <p>The median age at diagnosis of HL and BC was 25.3 and 45.3 years, respectively. The median interval to develop BC was 16.1 years. Eleven women (39.2%) had bilateral disease. Mode of detection of the index breast cancers was by mammographic screening in 17 patients (60.7%), palpable lump in 8 patients (28.6%), clinical examination in two patients (7.1%), and unknown in one patient (3.6%). Case-control analysis showed that histological features and prognosis of BC after HL were similar to those of primary BC, however, for BC after HL, mastectomy was the predominant surgery (<it>P </it>= .001) and adjuvant radiotherapy and anthracycline-based chemotherapy were less frequently used as compared to primary BC (<it>P </it>< .001 and .003, respectively).</p> <p>Conclusion</p> <p>The previous history of HL does not appear to be a poor prognostic factor for BC occurring thereafter.</p