Friend lymphatic leukemia virus-induced autoimmune hemolytic anemia with glomerulonephritis in the rat

WKA/Mk rats injected with Friend lymphatic leukemia virus at birth developed a runt ing syndrome which was associated with a high incidence of hemolytic anemia. The anemia was characterized by the presence of incomplete anti-erythrocyte autoantibodies detected by the direct antiglobulin test and the indirect enzyme-augmented hemagglutination assay, and, in some cases, was followed by glomerulonephritis. This system in the rat may represent a new model of autoimmune hemolytic anemia in man.     

Dynamics of lymphocytic subpopulations in Friend leukemia virus-induced leukemia

The in vivo roles of the immunosurveillance mechanism of the host against leukemia induced by Friend leukemia virus (FLV) were examined. The significance of T-cells in host defense against FLV-induced leukemia was indicated by the fact that thymus-deprived C57BL/6N-nu/nu mice were sensitive to FLV, although normal C57BL/6N mice were, as already reported by many authors, resistant to FLV. In relation to the role of T-cells on the onset of FLV-induced leukemia, the population dynamics of the lymphocytic subpopulations of the systemic lymphoid organs after FLV injection in FLV-resistant C57BL/6N mice were examined in comparison with the dynamics in FLV-sensitive strains, C57BL/6N-nu/nu mice and normal C3H/HeN mice. In this system, Lyt-1+2- helper T-cells in the spleen of FLV-resistant C57BL/6N mice increased in number after FLV injection. The number of immunoglobulin positive cells did not remarkably change in FLV-resistant C57BL/6N mice after FLV injection, whereas the number increased in the lymph node of FLV-sensitive C3H/HeN mice. The results indicated that a major contribution to the relative susceptibility and resistance of the host to FLV was controlled by the capacity to mobilize T-cells to the spleen in an early stage of disease, although the interaction of these T-cells with other immune cells may play an important role in mediating host resistance to FLV-induced disease.     

Spontaneous regression of Friend virus-induced erythroleukemia. II. regression of Friend murine leukemia virus-induced lymphocytic leukemia.

We characterized several aspects of spontaneous regression of lymphocytic leukemia in mice. The disease, induced by the helper murine leukemia virus (MuLV) component obtained from the regressing Friend virus complex (RFV), was characterized by spleen and lymph node enlargement, thymus involvement, and anemia. Leukemia regression occurred in about 25% of infected mice and resulted in the return of lymphoid organs to near-normal weight and normal histology and the recovery from anemia. A tenfold to 1,000-fold decrease in virus titer was seen in those mice in which leukemia regressed when compared to leukemic animals, although infectious virus was still recoverable from apparently normal spleens. The sera of mice in which leukemia regressed contained potent virus-neutralizing activity that was associated mainly with immunoglobulins. These studies firmly supported the evidence that the regressing phenotype of RFV was due to its helper MuLV component (MuLV-RF).     

Subtypes of T-cell chronic lymphatic leukemia

Thirteen cases of T-cell chronic lymphatic leukemia (T-CLL) (including T-cell prolymphocytic leukemia) are presented. Five subtypes were distinguished according to morphologic and functional parameters of the leukemic cells: prolymphocytic; lymphocytic, small; lymphocytic, Sézary-like; lymphocytic, abundant cytoplasm; lymphocytic, abundant cytoplasm and granules. The subtype can be recognized by light and by electron microscopic investigation. Cytochemistry (APh and ANAE) may be helpful to delimit T-CLL from B-CLL, and acid phosphatase to recognize the subtype characterized by abundant cytoplasm and granules. Membrane marker investigations support the diagnosis of T-type CLL. When functional properties of the leukemic cells were tested, cells of one patient (T-PLL) were shown to help in B-lymphocyte differentiation and Ig-secretion, whilst the cells of a second patient (lymphocytic, abundant cytoplasm and granules) were proven to act as effectors in natural killing and antibody-dependent cytotoxicity. The T-helper lymphocyte nature of some of the leukemic cells was supported by demonstration of the Fc mu-receptor in three cases. In one of these patients, monoclonal IgM was detected in the serum. Response to therapy and prognosis were rather poor in this limited number of patients when compared with B-CLL.     

Erythroid leukemia induced by Friend lymphatic leukemia virus in T-cell-depleted mice.

BALB/c mice depleted of T-cells by thymectomy at 3 to 5 days of age and by treatment with antithymocyte serum were inoculated with the lymphatic leukemia virus derived from Friend virus. After a long latent period, these animals developed erythroid leukemia. In contrast, intact control mice inoculated with Friend virus-associated lymphatic leukemia virus developed typical thymic (T-cell) lymphomas. Cell-free virus prepared from leukemic T-cell-depleted animals induced lymphoid, myeloid, and erythroid leukemias in intact mice. The erythroid leukemia-inducing virus differed from the spleen focus-forming component of Friend virus in its long latent period (88 to 225 days) and in its inability to induce spleen foci. End-point dilution experiments suggested that a hitherto undescribed component of the Friend virus complex might be responsible for these late-appearing erythroid leukemias.     

Immunotherapy of murine leukemia. VIII. Efficacy of passive serum therapy of Friend leukemia virus-induced disease in immunocompromised mice

Previous studies have demonstrated that the passive therapy of Friend murine leukemia virus (F-MuLV)-induced disease with chimpanzee anti-F-MuLV serum is accompanied by the development of host antiviral humoral and cellular immunity, the latter measurable in adoptive transfer protocols and by the ability of serum-protected mice to resist virus rechallenge. The present study was designed to further examine the contribution of various compartments of the host immune system to serum therapy itself, as well as to the acquired antiviral immunity that develops in serum-protected mice, through the use of naturally immunocompromised animals [e.g., nude athymic mice and natural killer (NK)-deficient beige mutant mice] or mice treated with immunoabrogating agents such as sublethal irradiation, cyclophosphamide [Cytoxan (Cy)], cortisone, and 89Sr. The studies in nude mice indicate that while mature T-cells are not needed for effective serum therapy, they do appear to be necessary for the long-term resistance of serum-protected mice to virus rechallenge and for the generation of the cell population(s) responsible for adoptive transfer of antiviral immunity. Furthermore, this acquired resistance is not due to virus neutralization by serum antibodies since antibody-negative, Cy-treated, serum-protected mice still reject the secondary virus infection. Lastly, while the immunocompromise systems examined did effect various host antiviral immune responses, none of them, including the NK-deficient beige mutation, significantly diminished the efficacy of the passive serum therapy of F-MuLV-induced disease.     

Proliferation of infected lymphoid precursors before Moloney murine leukemia virus-induced T-cell lymphoma

NFS/N mice inoculated with Moloney murine leukemia virus (M-MuLV) developed T-cell lymphoma after a 10-week latent period. Expression of lymphoid differentiation antigens, appearance of M-MuLV-encoded cell surface antigens, and rates of cellular proliferation were measured in splenic and bone marrow subpopulations during this latent period. At 2 weeks of age, Thy-1-and surface immunoglobulin-negative null cells of spleen and bone marrow expressed M-MuLV antigens whereas T- and B-lymphocytes did not. During the 3d and 4th weeks, the number of splenic null cells increased to six times the number found in uninfected controls. These null cells included the precursors of lymphocytes and hematopoietic cells. For the remainder of the latent period, the percentage of null cells undergoing proliferation was three times greater in the infected mice, while the total number of null cells remained constant. This proliferation was not accompanied by terminal differentiation or emigration of mature cell types from the spleen. Proliferation was substantially delayed in CBA mice, which are resistant to lymphoma induction.     

Poorly expressed CD2 antigen on the leukemic cells of adult T-cell leukemia and chronic lymphocytic leukemia of T-cell lineage

Adult T-cell leukemia (ATL) and T-cell chronic lymphocytic leukemia (T-CLL) are hematologic neoplasms in differentiated stages of peripheral mature T cells. This is suggested by the presence of CD2 (E rosette receptor) and mature and/or pan-T cell membrane surface antigens on their leukemic cells. We recently encountered one patient with ATL and another with T-CLL; their leukemic cells poorly expressed CD2 antigens, but clinical presentation, morphology of the leukemic cells and other marker studies were characteristic of either ATL or CLL. The clinical significance of the poor expression of CD2 remains to be further studied. The two patients reported here died of severe complications 4 and 9 weeks after diagnosis. The poor expression of CD2 in the peripheral T cells in these neoplasms is likely to indicate an aggressive nature of the disease.     

Establishment and cytological characteristics of two in vitro T-cell lines derived from a child with acute lymphatic leukemia and a man with adult T-cell leukemia in Japan

Two permanent T-cell leukemia lines designated KH-1 and KH-2 were established from the peripheral blood of a 9-year-old boy with acute lymphoblastic leukemia and a 47-year-old man with adult T-cell leukemia (ATL). No T-cell growth factor was used. KH-1 cells grew as single cells and KH-2 cells formed clusters in suspension culture. E-rosette formation, the absence of immunoglobulin determinants and Epstein-Barr-virus-associated nuclear antigen, and the presence of T-cell antigens revealed by monoclonal antibodies were characteristics of these cell lines as in other established T-cell leukemia lines. Chromosome analysis at the beginning revealed mosaic presence of cells with 46, XY, t (8q+; 15q-) and 46, XY which was later completely replaced by the latter karyotype in KH-1, and abnormal karyotype, 47, XY, +3, t (8q-; 10p+) was maintained throughout the period of in vitro passage in KH-2. The donor patient of KH-2 formerly lived in the south-western part of Japan where ATL is considered endemic and numerous type-C virus particles were detected electron microscopically, in KH-2 cell pellets.     

Friend virus-induced inhibition of eosinophil granulocyte exudation in mice

Exudation of eosinophil polymorphonuclear leukocytes (E-PMN) in response to tetanus toxoid (TT) was studied in DBA/2HaD mice with erythroleukemia induced by Friend virus (FV). The inhibition of exudation that developed was independent of increased levels of serum corticosteroids and occurred in surgically adrenalectomized mice. Thus it was independent of steroid-induced effects on E-PMN. The accumulation of neutrophil polymorphonuclear leukocytes (N-PMN) in TT-induced exudates was unaltered. Furthermore, N-PMN exudation in response to other inflammatory stimuli was similarly unimpaired in virus-infected mice, which confirmed the specificity of the inhibition for E-PMN. The virus entity in the FV complex responsible for the effect was not identified. Friend murine leukemia virus, the indigenous helper virus for the defective spleen focus-forming virus, alone, was incapable of inducing the inhibition. It is possible that the lack of participation of E-PMN in TT-induced immune inflammatory exudates in FV-infected mice reflects an unresponsiveness that contributes to the development and progression of leukemia in FV-infected mice.     

In vitro inhibition of cell-mediated cytotoxicity against syngeneic Friend virus-induced leukemia by immunoregulatory alpha globulin.

Immunoregulatory alpha-globulin (IRA) derived from normal human plasma decreased cytotoxic reactivity as measured by an in vitro 5-iodo-2'-deoxyridine release assay of immune mouse lymphocytes against the syngeneic Friend virus-induced leukemia, FBL-3. This inhibitory effect depended on the dose of IRA used and was not due to the cytotoxic effects of IRA on the effector cells or target tumor cells. We also found elevated levels of serum alpha-gloubins in FBL-3 tumor-bearing mice as compared to normal mice. These data and the demonstration of decreased specific cytotoxic reactivity in FBL-3 tumor-bearing mice suggest that IRA functions in the suppression of the host's immune response against tumors.