Hapten-carrier relationships of isoantigens. A model for immunological maturation based on the conversion of haptens of carriers by antibody.

In chickens, erythrocyte isoantigens have hapten-carrier relationships. Specific anticarrier antibody depresses the immune response to the carrier and enhances the immune response to the hapten. Antigenic determinants of "haptenic" isoantigens behave as carriers if they are coated with specific antibody. It is postulated that every humoral antibody response involves the cooperation of a carrier with a hapten and the progressive conversion by antibody of haptens to carriers. Thus a carrier is viewed as an antigenic determinant which is coated with antibody. The antibody-forming cell only synthesizes antibody to the uncoated haptenic determinants. The consequences of this interpretation for the development of immunological maturity and the secondary immune response are discussed.

Passive antibody and the immune response. Factors which determine enhancement and suppression.

The isoimmune response of fowl inoculated with RBC coated with antibody was investigated. Anti-B antiserum from a single animal was used to coat different donor type RBC. With each donor type RBC the immune response to the coated determinants is suppressed. Enhancement of the immune response to noncoated determinants occurs when they are products of an allelic gene or belong to a different blood group system. Coating some B antigen determinants suppresses the response to noncoated determinants of the same antigen, i.e., determinants which are products of the same B gene. Varying the quantity of passive antibody revealed that the degree of suppression and the degree of enhancement are negatively correlated. These findings support the concept that antibody-coated determinants function as carrier for noncoated determinants, provided a certain physical association exists between them. A further interpretation of these studies is that in certain situations an antibody to one antigen may interfere with events which lead to an immune response to a different antigen. The possibility, that the protection afforded by ABO incompatibility against Rh isoimmunization is because of a similar phenomenon, is discussed. A hypothesis is presented which states that where the immune response to certain antigens behaves as a dominantly inherited trait, and is associated with histocompatibility type, the nonresponder animals possess an antibody (perhaps cell bound) which interferes with the response to determinants for which it does not have specificity. Responders are assumed to lack this antibody because it has specificity for their major histocompatibility antigens.

Antibody-forming cells: population patterns after simultaneous immunization with different isoantigens.

Spleen cells were obtained from chickens stimulated simultaneously with different erythrocytic antigens, and the proportions producing one and two antibodies were determined by the hemolytic-plaque technique. Most cells from birds immunized with two antigens of the same system (B) appeared to produce only one antibody. In a population of cells from birds immunized with antigens of different systems (A and B), a relatively high proportion of cells produced two antibodies.

Adjuvant activity of erythrocyte isoantigens.

Erythrocyte isoantigens determined by the B blood-group locus of chickens enhance the immune response to weak isoantigens. This adjuvant action occurs if the antigens are present on the same erythrocyte, and the recipients are capable of responding immunologically to the B antigens.

Rous sarcomas in chickens: enhanced growth coexisting with concomitant immunity.

Chickens bearing Rous sarcoma virus-induced tumors in one wing did not develop new tumors when subsequently inoculated with Rous sarcoma virus in the other wing. However, the second inoculation of Rous sarcoma virus caused accelerated growth of the established tumors. This phenomenon was found to be bursa-dependent. Paradoxically, established tumors in bursectomized chickens grew at a diminished rate if the chickens were reinoculated with Rous sarcoma virus.

Transplantable Marek's disease lymphomas. II. Variable tumor immunity induced by different lymphoblastoid cells.

The effectiveness of cells from 6 different Marek's disease (MD) lymphoblastoid cell lines to induce immunity to syngeneic transplantable MD lymphomas was investigated in 2 related inbred lines of White Leghorn chickens (lines G-B1 and G-B2) that have different major histocompatibility complex (MHC) genotypes. Cells from 2 line G-B1 lymphomas (MDCT-NYM1 and MDCT-UG1) and 1 line G-B2 lymphoma (MDCT-UG2) were used for challenge. Three of the lymphoblastoid cell lines tested were developed from these lymphomas. Growth of palpable lymphomas was lowest among G-B2 chickens immunized with syngeneic lymphoblastoid cells. Protection against the early lethal effects of the highly virulent transplantable lymphomas was greatest in both lines of chickens when the lymphoblastoid cells were syngeneic with the hosts. Lymphoblastoid cells of unknown MHC type either failed to induce immunity to the lymphomas in both lines or protected some line G-B2 chickens challenged with syngeneic MDCT-UG2 lymphoma cells.

Marek's disease in immunosuppressed chickens: growth of a transplantable lymphoma and development of the disease by natural exposure.

Evidence indicated that treatment of chickens with Cytoxan at hatching (bursectomy) had little effect on the development of transplantable Marek's disease (md) lymphoma. Cytoxan treatment of chickens at 2 and 3 weeks of age, however, apparently reduced the incidence of visceral tumors in chickens naturally exposed to MD. Amelioration of MD in immunosuppressed chickens was possibly mediated through suppression of MD-induced T-cell proliferation.

Variation in histology and growth characteristics of transplantable Marek's disease lymphomas.

A comparative study was made of the histology and growth characteristics of three different Marek's disease virus-induced transplantable lymphomas. These lymphomas were developed previously in related inbred chicken lines G-B1 and G-B2. The UG1 lymphoma was developed by serial i.m. passage in G-B1 chickens, and the UG2 and UG4 lymphomas were developed similarly in G-B2 chickens. While all three lymphomas grow progressively and cause rapid death in syngeneic hosts, differences in pathogenicity exist. For equivalent passage levels, the mean time to death of syngeneic chickens inoculated with 10(5) lymphoma cells was 10.8, 12.8, and 16.3 days postinoculation for UG1, UG2, and UG4, respectively. Histological features examined at the light microscopic level included tumor necrosis, muscle invasion, mitotic activity, and presence of heterophils (comparable to mammalian neutrophils). The UG2 lymphoma was characterized by a high degree of necrosis during all stages of growth. This feature was least pronounced in UG4 lymphomas, which generally grow to a much larger size than UG1 or UG2 lymphomas. Vascular invasion was a feature of UG2 lymphoma cells in skeletal muscle and may account for the necrosis. The UG2 cells, which are somewhat larger than UG4 cells, occasionally contained cytoplasmic vacuoles. While the number of heterophils was highest in early stages of UG2 tumors, the role of these cells is unclear. The findings provide the basis for utilizing the transplantable lymphomas as a model to study mechanisms underlying variable pathogenicity of malignant tumors.

Effects of vaccination for Marek's disease on growth of a Marek's-virus-induced transplantable lymphoma in syngeneic and allogeneic chickens.

A study was made of the effects of vaccination with turkey herpesvirus on the growth of tumors following inoculation of lymphoma cells induced by Marek's disease virus (MDV). The cells used were from a transplantable MDV-induced lymphoid tumor (MDT-198) maintained by passaging in syngeneic hosts. Vaccination did not prevent progressive tumor growth or alter subsequent mortality among syngeneic recipients of MDT-198 cells. With allogeneic recipients, however, vaccination had a significant protective effect in that progressive tumor growth and mortality were markedly lowered. Both development of visceral lymphomas and atrophy of thymus and bursa were found at necropsy in both syngeneic and allogeneic hosts when progressive tumor growth occurred at the site of inoculation. The results suggest that it is unlikely that the primary and effective component of turkey-herpesvirus-induced protection against Marek's disease is directed against Marek's-disease-tumor-specific antigens.

Transplantable Marek's disease lymphomas. I. Growth characteristics during development in two inbred lines of chickens.

Lymphomas developed in the pectoral muscle of most chickens inoculated with cells from primary Marek's disease virus-induced visceral tumors obtained from chickens of the same inbred line. However, serial passaging of the lymphoma cells in histocompatible hosts generally resulted either in an eventual absence of tumor formation at the inoculation site or in tumor regression. Exceptions occurred in two experiments, where tumors grew rapidly and the hosts died early. Subsequent passaging of cells from these tumors into syngeneic recipients resulted in the development of two new transplantable Marek's disease (MD) lymphomas. These lymphomas, which were developed in chickens of related inbred lines--G-B1 and G-B2--were designated MDCT-UG1 and MDCT-UG2, respectively. Cells from the transplantable lymphomas possess different major histocompatibility complex (MHC) antigens, since G-B1 and G-B2 chickens have different MHC genotypes. A change in the cellular composition during a particular passage for both lymphomas, as indicated by marked increases in the percentage of cells possessing a MD tumor-associated surface antigen (MATSA), suggests that each arose as a result of the emergence and selection of a highly malignant clone of cells.

Marek's disease virus-induced transient paralysis in chickens: demonstration of vasogenic brain oedema by an immunohistochemical method.

The presence of vasogenic brain oedema and its distribution in Marek's disease virus (MDV)-induced transient paralysis (TP) were determined in genetically resistant and susceptible inbred White Leghorn chickens. MDV-inoculated TP-susceptible chickens with nervous signs (9 days post-inoculation) had severe vacuolation of cerebellar white matter and associated diffuse leakage of albumin and IgG. The serum protein leakage was associated morphologically with a vasculitis and intramural pseudocyst formation in the walls of blood vessels cuffed by mononuclear cells. This transient vasculitis and resulting vasogenic oedema coincided with the temporary neurological signs seen in TP-susceptible chickens. The vasculitis and vasogenic oedema were not present in brain tissue from recovered MDV-inoculated TP-susceptible chickens, MDV-inoculated TP-resistant chickens, or uninoculated control chickens from either line.

Marek's disease virus-induced transient paralysis: clinical and electrophysiologic findings in susceptible and resistant lines of chickens.

Results of neurologic examination, EEG, and motor nerve conduction velocity quantitation were analyzed in a line of chickens susceptible to Marek's disease virus-induced transient paralysis and compared with findings in a resistant line. Both lines were evaluated on the day before virus inoculation (day 1; base line) and on days 12 and 19. The susceptible birds frequently became depressed and paretic on day 11 or 12 and then recovered, and the resistant line rarely was affected clinically. The EEG of clinically affected birds from the susceptible line correlated well with the clinical course of the disease. Electroencephalographic abnormalities were absent in these birds at base line, evident at 12 days, and had remitted when they were reevaluated on day 19. The pattern in these clinically affected birds was predominantly low voltage-fast activity with frequent spikes. In contrast, the EEG recorded in resistant birds remained essentially the same throughout the study. Mean motor nerve conduction velocity values for the 2 lines of birds did not differ significantly when compared either between or within groups. These findings indicate that Marek's disease virus-induced transient paralysis may be an inflammatory encephalopathy.

Motor nerve conduction velocity in normal chickens.

Muscle potentials evoked by proximal and distal tibial nerve stimulation were evaluated and used to calculate motor nerve conduction velocity in 65 chickens. Two potentials analogous to the M and F waves recorded in persons consistently were evoked. The mean tibial motor nerve conduction velocity +/- SD of the birds was 32.3 +/- 4.0 m/s. This value varied significantly (P less than 0.05) with both age and cloacal temperature.

Influence of the major histocompatibility complex on tumor regression and immunity in chickens.

A number of studies show that major histocompatibility complex (MHC) genes control host immune responses to viral-induced chicken tumors. The MHC gene-controlled responses to malignant neoplasms caused by Rous sarcoma virus, lymphoid leukosis virus and Marek's disease virus are reviewed. Genes that determine regression of Rous sarcomas and resistance to development of lethal Marek's disease lymphomas appear to map within the B-F region of the MHC. In some cases, genetic complementation of both MHC genes and non-MHC genes may be responsible for regression of tumors. Metastasis of Rous sarcoma cells is also influenced by the host's MHC genotype. Background genes can modify the specific MHC gene effect on resistance to progressive growth of Rous sarcomas and Marek's disease lymphomas. Studies showing that MHC-restricted immunity may be important in cytotoxic T cell reactions to virus-infected and/or transformed chicken cells are discussed. The MHC-restricted cytotoxicity, whereby the T cells and target cells must share one MHC haplotype for in vitro killing to occur, suggests that the T cells have receptors that recognize virus-altered self MHC antigens. This may be an important immune surveillance mechanism for limiting the proliferative growth of virus-induced tumors in chickens.

Independence of chicken major histocompatibility antigens and tumor-associated antigen on the surface of herpesvirus-induced lymphoma cells.

Capping of chicken major histocompatibility (MHC) antigens on normal thymus, spleen, and peripheral blood leukocytes was demonstrated, although MHC antigens appeared to be present on only 15 to 18% of normal thymus cells. MHC antigen capping also occurred on cells from a Marek's disease herpesvirus-induced transplantable lymphoma (MDCT-NYM1). Capping of a Marek's disease tumor-associated surface antigen (MATSA) could be induced on MDCT-NYM1 lymphoma cells as well as on cells of two Marek's disease in vitro lymphoblastoid cell lines (MDCC-MSB1 and MDCC-LS1). Cocapping of MHC antigens and MATSA did not occur on MDCT-NYM1 lymphoma cells. The results suggest that MHC antigens and MATSA are not structurally associated on the cell membrane.