Recent studies indicate that oncogenes may be involved in determining the sensitivity of human cancers to chemotherapeutic agents. To de®ne the eect of HER-2/neu oncogene overexpression on sensitivity to chemotherapeutic drugs, a full-length, human HER-2/neu cDNA was introduced into human breast and ovarian cancer cells. In vitro dose-response curves following exposure to 7 dierent classes of chemotherapeutic agents were compared for HER-2-and control-transfected cells. Chemosensitivity was also tested in vivo for HER-2-and control-transfected human breast and ovarian cancer xenografts in athymic mice. These studies indicate that HER-2/neu overexpression was not sucient to induce intrinsic, pleomorphic drug resistance. Furthermore, changes in chemosensitivity pro®les resulting from HER-2/neu transfection observed in vitro were cell line speci®c. In vivo, HER-2/neu-overexpressing breast and ovarian cancer xenografts were responsive to dierent classes of chemotherapeutic drugs compared to control-treated xenografts with no statistically signi®cant dierences between HER-2/neu-overexpressing and nonoverexpressing xenografts. We found no instance in which HER-2/neu-overexpressing xenografts were rendered more sensitive to chemotherapeutic drugs in vivo. HER-2/neu-overexpressing xenografts consistently exhibited more rapid regrowth than control xenografts following initial response to chemotherapy suggesting that a high rate of tumor cell proliferation rather than intrinsic drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in human cancers.

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SummaryWe present evidence that a single T cell clone can recognize at least five different overlapping peptides, each with its distinct core structure, in the context of the same major histocompatibility complex (MHC) molecule. Distinct core residues are crucial for triggering the T cell receptor (TCR) in each case. These results suggest that the TCR (a) has multiple sets of contact residues for alternative peptide-MHC ligands, the binding to any one of which can trigger the cell; and/or (b) is able to attach to the peptide-MHC complex in more than one orientation. In this sense, the TCR is a multisubsite structure capable of being stimulated by a variety of peptide ligands associated with the same MHC molecules.T CRs recognize an antigen only when the antigen's peptide fragments are lodged in a groovelike site on MHC molecules (1). How do the TCRs interact with the peptide-MHC complex? The answer is not clear because the crystal structure of the TCR-peptide-MHC complex still has not been solved. In the meantime, several models for the ternary molecular interaction have been proposed in which the CDR3 loops (encoded by the V-(D)-J junctional region) of both chains of the TCR molecule bind the nominal peptide, whereas the germline-encoded CDR1 and CDR2 loops bind the oe helices of the MHC molecule, which flank its peptidebinding groove (1-4).Using variants of each of the three participating molecules of the TCR-peptide-MHC complex, extensive attempts have been made to test these predictions (4-9). The results from these studies have neither entirely supported nor contradicted these models; nevertheless, several characteristics of the interacting trimolecular complex have emerged. It thus seems clear that a single peptide-MHC ligand can induce several distinct TCR molecules, with each TCR molecule recognizing a distinct aspect of the peptide in the MHC groove. Different TCR molecules displaying specificity for the same peptide-MHC ligand may interact with different and overlapping residues of the peptide (4-8). In addition, studies with MHC mutants at the residues pointing inward along the wall of the peptide-binding groove of the MHC molecule showed that different TCRs displaying identical specificity for the ligand were differentially affected by such mutant MHC molecules (8). These results emphasize that alterations of the particular conformation of the peptide-MHC complex, induced by the association of the peptide with the altered peptidebinding groove, can result in loss of recognition. Taken together, these results indicate strict constraints in interactions between the TCR molecule and the peptide-MHC complex.However, how precise are the requirements for peptide structure, distribution of charge and hydrophobicity for a peptide to be a stimulatory one for a given TCR? Can only a single sequence from the antigen associated with a given MHC molecule meet the constraints of TCR recognition? We have asked this question by using a previously reported panel of I-A arestricted sperm whale myoglobin (SWM) 1 peptid...

Linkage of AIDS and cancer registries has indicated an increase in T-cell lymphomas among individuals infected with the HIV. The characteristics of T-cell versus B-cell lymphoma in HIV-infected patients are not well described. Retrospectively, 11 cases of T-cell lymphoma were identified from the AIDS-Lymphoma Registry at the University of Southern California. These patients were compared with 418 consecutive HIV-seropositive patients with B-cell lymphoma diagnosed and treated within the same time period. T-cell lymphomas comprised 3% of all AIDS lymphomas. Pathologic types included peripheral T-cell lymphoma in 5; anaplastic large cell lymphoma in 3; and angioimmunoblastic, enteropathy type, and human T-cell lymphotropic virus-I-related adult T-cell lymphoma/leukemia in 1 case each. No differences in demographic characteristics, history of prior opportunistic infection, or immunologic characteristics were observed between T-cell and B-cell cases. Extranodal involvement of the skin (36% vs. 2%, P < 0.001) and bone marrow (45% vs. 15%, P = 0.019) was significantly more common in T-cell lymphomas. The median survival of patients with T-cell lymphomas was not significantly different from that of B-cell lymphoma patients (10.6 vs. 6.6 months, P = 0.13). T-cell lymphomas in HIV-infected patients represent a spectrum of pathologic types. T-cell lymphomas differ from B-cell cases in terms of a higher propensity for skin and bone marrow involvement. The median survival of patients with T-cell lymphoma is comparable to that of patients with B-cell AIDS-related lymphoma.

Sunullal'yGiven the vast potential for diversification of the T cell receptor (TCR) repertoire and the fact that V~ mice exist in the wild, it would have been predicted that in spite of the absence of 10 TCR. V~ gene segments, V~ mice would still have been able to produce an antigen-specific T cell response to all determinants. We have recently shown that V~ mice, with a wild-type TCR Va repertoire, respond to peptide 110-121 of sperm whale myoglobin, with a majority of T cells expressing TCR V~8.2 and restricted to a hybrid I-AO/I-E d major histocompatibility complex molecule, and a smaller number of T cells expressing TCR Va8.1 and restricted to the I-A d molecule. However, V~ mice, lacking members of the TCR V~8 gene family, responded only with I-Ad-restricted T cells. Thus, it appeared that the I-Ad-restricted response was less constrained, or more plastic. We now show that the two separate panels of I-Aa-restricted T cell hybrids derived from V~ or V~ mice in fact recognize distinct determinants within the same peptide 110-121. The determinant recognized by V~ T ceils is NH2 terminal (core: 110-118) with an absolute requirement for the residue Ala-110 for a successful interaction with TCRs. On the other hand, V~ T cells recognize the COOH-terminal region (core:112-118) on the same peptide with an absolute requirement for COOH-terminal residue 118. In the dominance hierarchy displayed by the three distinct determinants of peptide 110-121, V~ mice cannot recognize the two most dominant: the hybrid I-Aa/I-Ea-restricted determinant and the COOH-terminal, I-Aa-restricted determinant. They instead respond with T cells specific for a third, distinctly NH2-terminal determinant. Our results show a strict association between recognition of a particular specificity and TCR Va usage. This evidence suggests that even when a small peptide induces a heterogenous group of TCR V~s, this need not be considered evidence for plasticity. Rather, at the level of individual determinants within the peptide, the results can point in the opposite direction, towards serious constraints in recognition at the level of V~ expression.