In vivo effects of anti-Ia alloantisera. I. Elimination of specific suppression by in vivo administration of antisera specific for I-J controlled determinants.

Abstract

The helper and suppressor regulatory activities exerted on antibody responses by T lymphocytes are associated with subregions of the I region of the murine H.2 (major histocompatibility) complex. Using antisera defining Ia antigens, raised by immunization between congenic pairs of mice differing at the ! region, specific suppressor T cells (1, 2) and their soluble and mediators (3-5)have been shown to bear I-J subregion coded determinants, whereas certain helper (enhancing) factors and possibly helper cells possess I-A coded determinants (6, 7).i Analysis of the effects of such specific anti-Ia antisera on immune responses can, therefore, provide information concerning the regulatory functions of the various ! region products, This approach has been used in various model systems, and several investigators have reported marked inhibition of in vitro lymphocyte reactivity by distinct anti-la antisera (8-12). It was thus appropriate to determine whether such antisera would also alter in vivo immune responses. We reported recently (13) that microliter amounts of alloantisera against I k and I # gene products were able to potentiate primary IgM and IgG in vivo plaque-forming cell (PFC) 2 responses to suboptimal immunogenic doses of sheep erythrocytes (SRBC) in A/J and BALB/c mice, respectively. The same immunopotentiating activity was observed with an anti-I-J k antiserum in A/J mice. Further studies revealed that in vivo administration of the same anti-I-J k antiserum decreases tumor growth in A/J mice inoculated with a syngeneic methylcholanthrene-induced fibrosarcoma (14), known to elicit potent suppressor T-cell responses active in inhibiting antitumor immunity (15, 16). These observations raised the possibility that the potentiation of SRBC PFC responses observed with the anti-I-J k antiserum, *

A role for suppressor T cells in induction of self-tolerance.

“…In particular the I-J gene(s) do not appear to be typical of other class II histocompatibility genes. Nevertheless, despite present uncertainties concerning the physiological role of I-J (14), there is sound experimental evidence demonstrating that anti-I-J antibodies can be used to abrogate Ts function selectively without influencing the activities of other T-cell subsets (15,16). Thus, the demonstration here of increased susceptibility of anti-I-J-exposed mice to the induction of autoimmunity is consistent with a central role for Ts in mediating selftolerance.…”

“…Ts can be distinguished from other T-cell subsets by the fact that they carry the serologically defined I-J determinant (11) and, thus, can be selectively removed by antibodies with anti-I-J specificity (16 immunized with a single intraperitoneal injection of 2 x 10' normal RRBC which carry not only rat-specific antigens but also determinants with cross-reactivity for mouse erythrocytes (MRBC) as well (17). Blood was collected at intervals thereafter for measurement of antibodies to MRBC and RRBC.…”

Regulation of immune responses by I-J gene products. I. Production and characterization of anti-I-J monoclonal antibodies.

“…These findings were subsequently confirmed by Theze et al (9) for a poly(GluU~'l'yrt'~)(GT)-specific TsF and by Greene et al (10) for an azobenzene arsonate-specific TsF. Pierres et al (11,12) demonstrated that the administration of microliter quantities of anti-I-J serum to GT-suppressor strain mice allowed them to make a GT-specific antibody response apparently due to the elimination or inactivation of I-J-bearing Ts. Likewise, Greene et al (13) showed that alloanti-I-J, when administered to S1509a fibrosarcoma-bearing mice, caused regression of the tumor due to the inactivation of tumor-induced Ts.…”

Regulation of antibody heterogeneity by suppressor T cells: diminishing suppressor T cell activity increases the number of dinitrophenyl clones in mice immunized with dinitrophenyl-poly(Glu,Lys,Phe) or dinitrophenyl-poly(Glu,Lys,Ala).

“…Adult thymectomy (12), treatment with a low dose of cyclophosphamide (13), and administration of antisera directed at I-J region coded determinants of the murine major histocompatibility complex (10,11,14) have been used to selectively diminish suppressor T-cell activity. The reasons for the effectiveness of these procedures stems from the fact that the population of thymus-derived lymphocytes can be differentiated into subsets of cells, each subgroup sharing unique biological functions, cell-surface phenotypes, or physiological characteristics (15 We have previously demonstrated that in vivo administration of anti-I-J serum eliminates suppressor T-cell activity in two independent systems (11,14).…”

“…The antisera used in this study were raised in the following strain combinations: anti-Iad, (C3H X LG/ckc)F1 anti-C3H.OH; anti-I-Jk, [B1O.A(3R) X DBA/2]F1 anti-B1O.A(5R); and A anti-I-J3 (3R X 9R)F1 anti-B1O.HTT. The specificity and titer of the sera, including control absorption studies and the protocol for intravenous administration of antisera, were as described (10,11 Table 1, the numbers of Dnp-specific clones expressed in the antisera obtained from thymectomized animals are significantly greater than the numbers of anti-Dnp antibody-producing clones expressed in antisera from control mice in both primary and secondary antibody responses to Dnp-GLA or Dnp-GLL. The increased anti-Dnp antibody heterogeneity of antiDnp-GLA or anti-Dnp-GLt antisera of thymectomized animals is noted even though the antigen-binding capacities of the antisera from thymectomized animals are not significantly greater than the antigen-binding capacities of respective antisera from control mice.…”