Adoptive transfer of T cells reactive to minor histocompatibility antigens has the unmatched ability to eradicate malignant hematopoietic cells. Unfortunately, its use is hampered by the associated graft-versus-host disease. The critical issue of a possible dissociation of the antileukemic effect and graft-versus-host disease by targeting specific minor histocompatibility antigens remains unresolved because of the unknown nature and number of minor histocompatibility antigens necessary or sufficient to elicit anti-leukemic activity and graft-versus-host disease. We found that injection of T lymphocytes primed against a single major histocompatibility complex class I-restricted immunodominant minor histocompatibility antigen (B6dom1) caused no graft-versus-host disease but produced a curative anti-leukemic response. Avoidance of graft-versus-host disease required that no other host-reactive T cells be co-injected with T cells primed with B6dom1. Here we show that effective and non-toxic immunotherapy of hematologic malignancies can be achieved by targeting a single immunodominant minor histocompatibility antigen.

IntroductionOne hallmark of the adaptive immune system is that the thymus has been conserved as the primary T-lymphoid organ during 450 million years of evolution. 1 This level of conservation is remarkable when one considers that about 10 different organs have been used as primary sites of hematopoiesis in jawed vertebrates. 1 Thymic epithelial cells (TECs) derived from the third pharyngeal pouch are the main constituent of the thymic environment. 2 TECs provide 2 types of signals to thymocytes: T-cell receptor (TCR)-dependent and TCR-independent. [3][4][5] In conjunction with mesenchymal cells, TECs have a unique ability to provide TCR-independent interactions that are essential for several thymocyte developmental events but whose nature is still elusive. 2,[6][7][8][9] Indeed, studies in wild-type and TCR-transgenic euthymic and nude mice indicated that the efficiency of generating mature T cells was 100 to 1000 times less in nude compared to euthymic mice. 5 In contrast, TCR-mediated signals, dictating which TCR clonotypes are positively selected, can be supported by major histocompatibility complex (MHC)-peptide complexes displayed by other cell types. Thus, studies involving hematopoietic chimeras and thymus grafts have shown that hematopoietic cells can mediate positive selection of CD8 T cells in vivo. 5,10,11 In line with this, studies in tetraparental aggregation chimeras have demonstrated that the MHC of TECs is not required for efficient positive selection of MHC Ia-and MHC II-restricted T cells. 12 Moreover, under normal circumstances, preferential or exclusive positive selection on hematopoietic cells appears to be a general characteristic shared by many (if not all) MHC class Ib-restricted T cells. [13][14][15] These data indicate that the nonredundant role of TECs is to provide TCR-independent signals to thymocytes, but that TCR signals can be provided by other cells in the thymus and the periphery. 5,16 These considerations raise the question of whether the canonical influence of TECs on T-cell development is essential for survival. Would lymphocytes developing in a TEC-free milieu be functional and reach sufficient numbers to eradicate pathogens? Oncostatin M (OM)-transgenic mice represent a unique model to directly address this issue. Remarkably, chronic exposure to OM transforms the lymph node (LN) into a "primary" lymphoid organ whose ability to support T-cell development and to seed secondary lymphoid organs is similar to that of a normal thymus. 17,18 The lymphopoietic pathway modulated by OM is truly thymusindependent and takes place only in the LNs. 17,18 The proportions of double-negative, double-positive, and single-positive T cells in the OM ϩ LNs reproduce those found in a thymus, and the TCR repertoire of the single-positive cells is diversified. The effect of OM on extrathymic T-cell development in the LNs is probably due to some amplification of a cryptic pathway that is operative in conditions of defective thymopoiesis and was nicely characterized in nude mice. 19 Like normal LNs...

When presented alone, H7 a and HY antigens elicit CD8 T-cell responses of similar amplitude, but H7 a totally abrogates the response to HY when both antigens are presented on the same antigen-presenting cell. We found that H7a- and HY-specific T-cell precursors had similar frequencies in nonimmune mice and expressed similar levels of CD5. The H7a -specific CD8 T-cell repertoire harvested at the time of primary response showed highly restricted T-cell receptor (TCR) diversity. Furthermore, T cells specific for H7a and HY expressed equivalent levels of CD8 and TCR and displayed similar tetramer decay rates. The key difference was that anti-H7a T cells exhibited a much more rapid TCR:epitope on-rate than anti-HY T cells. Coupled with evidence that primed CD8 T cells limit the duration of antigen presentation by killing or inactivating antigen-presenting cells, our data support a novel and simple model for immunodomination: the main feature of T cells that exert immunodomination is that, compared with other T cells, they are functionally primed after a shorter duration of antigen presentation.

Adoptive transfer of allogeneic T cells has unmatched efficacy to eradicate leukemic cells. We therefore sought to evaluate in kinetic terms interactions between T cells and allogeneic leukemic cells. T cells primed against the model B6 dom1 minor histocompatibility antigen were adoptively transferred in irradiated B10 (B6 dom1 -positive) and congenic B10.H7 b (B6 dom1 -negative) recipients, some of which were also injected with EL4 leukemia/lymphoma cells (B6 dom1 -positive). A key finding was that the tissue distribution of the target epitope dramatically influenced the outcome of adoptive cancer immunotherapy. Widespread expression of B6 dom1 in B10 recipients induced apoptosis and dysfunction of antigenspecific T cells. Furthermore, in leukemic B10 and B10.H7 b hosts, a massive accumulation of effector/memory B6 dom1 -specific T cells was detected in the bone marrow, the main site of EL4 cell growth. The accumulation of effector/memory cells in recipient bone marrow was EL4 dependent, and its kinetics was different from that observed in recipient spleen. We conclude that strategies must be devised IntroductionT-cell immunosurveillance can prevent the development of several malignancies. Nevertheless, the common occurrence of neoplasia shows that cancer immunosurveillance is leaky. Not only are cancer cells commonly ignored by the immune system, they can induce anergy or deletion of tumor-reactive T cells. In addition, it has proven exceedingly difficult to elicit curative immune responses with tumor vaccines. 1,2 Several factors explain the disappointing results obtained in tumor vaccine trials: low immunogenicity of tumor-associated epitopes, absence of high-avidity tumorreactive T cells in the peripheral T-cell repertoire, location of cancer cells outside the secondary lymphoid organs, and microenvironmental features in the tumor cell stroma (physical barriers, cytokines) that hinder productive interactions between T cells and cancer cells. [3][4][5][6][7] Many drawbacks of tumor vaccines can be curtailed by the use of adoptive T-cell immunotherapy. 8 Indeed, the T-cell repertoire from an allogeneic donor comprises T lymphocytes that can recognize with high avidity non-self-epitopes expressed by recipient cancer cells. Furthermore, these T cells can be primed ex vivo against their target antigen before adoptive transfer. Injected cells can be self-major histocompatibility complex (MHC)-restricted T lymphocytes that recognize polymorphic MHC-associated peptides-that is, minor histocompatibility antigens (MiHA)-or they can be allo-MHC restricted. [9][10][11][12][13] Many clinical studies have shown that a single injection of allogeneic lymphocytes can eradicate up to 10 12 hematopoietic malignant cells. [14][15][16][17] The remarkable efficacy of adoptive T-cell immunotherapy in eradicating leukemia/lymphoma cells probably constitutes the most convincing evidence that T lymphocytes can cure established cancer. 15 Moreover, recent studies suggest that the efficacy of adoptive immunotherapy can be extended ...

No abstract