Effect of all-trans retinoic acid on induction, lethality and immunogenicity of murine methylcholanthrene-induced fibrosarcomas.

The effect of 200 micrograms doses of all-trans retinoic acid, given over a long duration (daily for 8 weeks, suspended for 3 weeks, then resumed daily for 4 weeks) or short duration (daily for 30 days), on the induction of fibrosarcomas in C57BL/6J mice by MCA was evaluated. A reduced level of carcinogenesis was observed with both lengths of retinoic acid treatment, since respective incidences of MCA fibrosarcomas were 63 and 61% of those in saline-treated controls. In other studies, the effect of all-trans retinoic acid on syngeneic growth of two experimental fibrosarcomas (B6 25 and B6 27, induced previously in C57BL/6J mice by MCA) was assessed. Retinoic-acid-treated mice were more resistant to higher doses of viable B6 27 (LD50 = 2.85) and especially B6 25 (LD50 = 3.80) than were corresponding saline- or corn-oil-treated controls (LD50 less than 2.0). The strength of resistance conferred by retinoic acid treatment thus varied considerably between these tumors, despite their common strain derivation and histopathological origin. Additional studies explored the effect on B6 27 growth of giving all-trans retinoic acid during either the sensitization or challenge stage of standard syngeneic immunogenicity tests. Mice given all-trans retinoic acid during sensitization displayed a markedly increased resistance to challenge with the immunospecific B6 27 tumor (LD50 = 5.30), compared to challenged controls that received saline (LD50 = 2.60) or corn-oil (LD50 = 2.55) during preimmunization. In contrast, when B6 27-preimmunized mice were treated with all-trans retinoic acid after challenge with homologous tumor, resistance to B6 27 (assessed by tumor growth rate and LD50 dose) was not increased but remained comparable to that of saline-or corn-oil-treated controls. While the mechanism(s) by which all-trans retinoic acid inhibits syngeneic growth of MCA tumors is unknown, our results support an immunostimulatory effect, evidenced by tumor resistance in both non-immune and specifically preimmunized syngeneic hosts.

Pretransplant bilateral nephrectomy and adjuvant operations.

Pretransplant bilateral nephrectomy by the posterior approach has been associated with minimal morbidity and mortality. Unfortunately the posterior approach is not applicable to all patients, e.g., patients with polycystic renal disease or patients who need simultaneously another intraperitoneal adjuvant operation such as splenectomy or vagotomy and pyloroplasty. This article presents 34 patients who had a transperitoneal bilateral nephrectomy and 29 other concurrent adjuvant operations. Morbidity and mortality are comparable to that reported for simple bilateral nephrectomy performed posteriorly. The reduction in morbidity and mortality was believed to be due to a careful application of the basic principles of surgical care and an appreciation of the special problems posed by patients on chronic hemodialysis. Perioperative care will be discussed in detail.

HLA frequencies in a Mexican American population.

HLA-A and -B antigens were determined for 300 unrelated Mexican-Americans and 300 unrelated Caucasians from San Antonio by the microlymphocytotoxicity technique, using lymphocytes isolated from freshly drawn peripheral blood. Haplotype frequencies for the Mexican American population were obtained directly, based on family studies, as well as estimated from phenotype data. The results revealed clear differences in the distribution of HLA antigens between Mexican American and Caucasian populations. The predominant HLA specificities in Mexican Americans were A2 and Bw35, while the most frequently observed haplotypes were A2-Bw35, A2-B12 and A2Bw40. Despite the distinct differences in HLA antigen distribution between Mexican American and Caucasian populations, genetic distance values, calculated from the HLA frequencies, were surprisingly low.

Demonstration in vitro of cytotoxic T cells with apparent specificity toward tumor-specific transplantation antigens on chemically induced tumors.

Chemically induced tumors of mice exhibit apparently unique antigenicity upon syngeneic transplantation into appropriately immunized hosts. An in vitro counterpart of this pattern in terms of specificity has not been reported. Data are presented that demonstrate that immune peritoneal exudates contain cells cytotoxic for the specific immunogen tumor but with rare exceptions, not toward other syngeneic methylcholanthrene-induced fibrosarcomas. Only tumors highly immunogenic by transplantation criteria induce cytotoxic PEC regularly; nonimmunogenic tumors consistently fail to do so. The effector cell responsible is eliminated by pretreatment with anti-Thy.1 but not anti-Ig plus complement. In concomitant experiments, PEC populations cytotoxic in vitro also conveyed adoptive protection against the specific tumor in syngeneic hosts. This in vitro assay appears to provide a tool for studying T cell-mediated cytotoxicity toward a set of unique surface antigens present on chemically induced tumors.

Relationship of tumor-specific transplantation antigens to the histocompatibility complex: dissociation of in vitro alloantigen expression and in vivo alloimmunity from tumor-specific transplantation antigen strength.

The studies reported here explore the relationship between tumor-specific transplantation antigens (TSTA) and (1) the expression of serologically defined specificities, and (2) the immunogenicity of H-2K- or H-2D-determined alloantigens on methylcholanthrene (MCA)-induced murine fibrosarcomas. Expression of H-2K and H-2D serologically-detected private specificities on groups of tumors raised in B10.A, B10.BR or B10.D2 strains varied greatly among tumors. No regular reciprocal or direct relationship to tumor TSTA strength was found. Each tumor, however, expressed H-2K or H-2D alloantigens stably as determined by direct cytotoxicity or absorption techniques. Even those tumors expressing little or no detectable alloantigen by serologic analysis were immunogenic in H-2K or H-2D incompatible congeneic hosts. This was assayed in terms of capacity to evoke primary or secondary tumor resistance, and to induce allo-antibody toward private H-2K or H-2D end specificities. An exception was that B10.BR tumors failed to induce anti-H-2Dk antibody despite strong surface alloantigen expression. While TSTA strength did not correlate with serologically detected alloantigen expression, TSTA strength did tend to correlate inversely with capacity to resist primary growth in the H-2K different host, and directly with resistance in the H-2D different host.

Asymmetry in the serological response and mixed lymphocyte reactions between C57Bl/6 and the congenic mutant C57Bl/6.CH-2ba [H(Zl)].

Asymmetry in the relationship between the H-2K mutant strain C57Bl/6.CH-2ba (H-2ba) and the wild-type congenic C57Bl/6 has been demonstrated both in MLR and serologically by haemagglutination. MLR between these strains, when B6 was the responder, was as strong as that toward allogeneic stimulator cells: H-2ba was regularly less responsive toward B6. Responses in both directions were increased, in terms of augmented proliferative responses, by prior immunization. In this context the MLR resembles that towards minor H-locus antigens rather than those controlled by the H-2 locus. Immunization of (H-2ba X BALB/c)F1 hybridgs with B6 lymphoid cells induced the production of a haemagglutinating antibody not directed toward any known H-2 specificity. The B6 haemagglutinogen, termed He, was present on B6 lymphoid as well as red blood cells. Segregation studies of F2 and back-cross progeny of (H-2ba X BALB/c)F1 hybrids suggest that the response to He is controlled by two Ir genes, one of which is linked to H-2.