Breast cancer in women with human immunodeficiency virus infection: pathological, clinical, and prognostic implications.

BACKGROUND: AIDS and breast cancer have become two important public health issues for women. Of interest is the prolonged survival of patients diagnosed with HIV infection as a result of the use of highly active antiretroviral therapy (HAART). With improved survival, we are likely to see more HIV-infected patients with breast cancer. METHODS: This study, which is a review of our experience at Harlem Hospital Center, New York, between 2000 and 2008, compared HIV-positive with HIV-negative breast cancer patients, with attention to tumor size, stage, grade, molecular markers and lymphovascular invasion, treatment, and patient survival. RESULTS: Only 63 of 370 patients with breast carcinoma were tested for HIV, and 6 of the 63 women tested positive for HIV. We, therefore, compared the clinical features and tumor characteristics seen in the 6 HIV-infected women with those of the 57 HIV-seronegative breast cancer patients. We found no differences in presentation, median age, and tumor morphology in the two groups of patients. When the patients in our previous report on 5 HIV-positive breast cancer patients were added to the present group, the overall 5-year survival rate among the 11 HIV-infected patients was 75%. Of note is the finding that HIV infection in premenopausal women was not associated with aggressive breast cancer subtypes with poor survival outcome. CONCLUSIONS: These results demonstrate that histological subgroups and 5-year survival appear similar among HIV-positive breast cancer patients.

Breast cancer in women with HIV/AIDS: report of five cases with a review of the literature.

BACKGROUND: The association of human immunodeficiency virus (HIV) infection with breast carcinoma is unclear. With improved survival of HIV-infected patients due to better understanding and treatment of the disease, there is likely to be an increase in incidence of breast cancer in women with HIV infection. METHODS: The medical records of 305 patients with breast cancer seen between January 1995 and December 2000 at Harlem Hospital Center, New York, where approximately 1,000 HIV-infected patients are treated yearly, were reviewed with attention to age, breast cancer stage at presentation, and patient survival. RESULTS: Breast cancer in the five HIV-infected patients has same median age distribution, disease stage, and pathologic characteristics as in the 300 HIV-indeterminate patients. Four of the five (80%) HIV-infected women compared to 79% in the HIV-indeterminate patients presented with early breast cancer (Stages I and II). Five-year survival in the HIV-infected patients is 80%, which is similar to the observed 70% 5-year crude survival rate in the indeterminate group. CONCLUSIONS: Our results do not support the recent reports suggesting that HIV infection is associated with poorly differentiated, aggressive disease with poor survival outcome. It remains unclear if breast carcinoma is directly linked to HIV infection.

New strategies in immune tolerance induction.

Induction of tolerance in clinical organ transplantation that will obviate the use of chronic immunosuppression and preserve host immune response to other antigens remains the goal of transplant research. The thymus plays a critical role in the ability of the immune system to discriminate between self- and nonself-antigens or harmful and harmless alloantigens. We now know that multiple factors determine how the immune system responds to a self-antigen or foreign antigen. These determinants include developmental stage of the host, stage of T-cell maturity, site of antigen encounter, type and maturity of antigen-presenting cells, and presence and type of costimulatory molecules. Our understanding of the mechanisms of T-cell interactions with peptide/ major histocompatibility complex in peripheral lymphoid organs has led to experiments that translate into peripheral T-cell tolerance. The induction of high-avidity peripheral alloreactive T cells in the early phase of organ transplantation makes it difficult to achieve long-term alloantigen-specific tolerance without the use of transient perioperative immunosuppression. Therefore, protocols that induce robust tolerance in rodent and nonhuman primate models involve the use of donor antigen combined with a short course of perioperative immunosuppression. These studies suggest that the underlying mechanisms of peripheral tolerance include deletion, anergy, immune deviation, and regulatory T cells. This review focuses on recent advances in tolerance induction in experimental animal models and discusses their relevance to the development of protocols for the induction and maintenance of clinical transplant tolerance.

CD4+CD25+ regulatory T cells mediate acquired transplant tolerance.

The Holy Grail of clinical organ transplantation is the safe induction of allograft tolerance. Transplant tolerance has been successfully induced in animal models. Since T cells play a pivotal role in graft rejection, modulating T cell function has been the primary focus of studies aimed at inducing transplant tolerance. Rodent models of transplant tolerance induction include central deletion and peripheral mechanisms involving activation-induced cell death (AICD), anergy, immune deviation, and production of regulatory T cells. These mechanisms are not mutually exclusive. Although clonal deletion and anergy limit self-reactive T cells in the thymus, these mechanisms alone are not sufficient for controlling self-reactive T cells in the periphery. There is now evidence that the adult animal harbors two functionally distinct populations of CD4(+) T cells; one mediates autoimmune disease and the other dominantly inhibits it. The latter cells express CD4, CD25 and CTLA-4. These thymus-derived T cells have recently been shown to mediate the induction and maintenance of transplant tolerance. These CD4(+)CD25(+) T cells are similar in origin, phenotype, and function to those that maintain natural self-tolerance and T cell homeostasis in the periphery. Against this background, is it possible that alloantigen specific regulatory T cells might be generated and expanded ex vivo before organ transplantation and then infused to induce long-term tolerance, perhaps without the need for chronic immunosuppression?

Role of CD41CD251 regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.

BACKGROUND: Immunization with allo-major histocompatibility complex peptide induces operational tolerance, whereas thymectomy abrogates this effect. We hypothesized that recent thymic emigrants with regulatory function are important in the induction of acquired transplant tolerance in this system. METHODS: In this study, we examined the possibility of restoring transplant tolerance to thymectomized (TMX) ACI recipients with concomitant adoptive transfer of syngeneic T cells indirectly primed with a single immunodominant Wistar Furth allo-major histocompatibility complex class I peptide (peptide 5, residues 93-109) and unmodified thymocytes or CD4+CD25+ thymic T cells. RESULTS: Co-transfer of in vivo allopeptide-primed T cells and naive syngeneic thymic T cells on day -7 restored permanent acceptance of cardiac allografts to 70% of transiently antilymphocyte serum-immunosuppressed TMX recipients. Similarly, the adoptive transfer of allopeptide-primed T cells led to 100% donor-specific permanent graft acceptance among transiently antilymphocyte serum-immunosuppressed TMX recipients with renal subcapsular syngeneic thymic grafts. To demonstrate the role of regulatory T cells among new thymic emigrants in the induction of tolerance, we showed that the co-transfer of CD4+CD25+ but not CD4+CD25- thymic T cells with allopeptide-primed syngeneic T cells restored tolerance to TMX recipients. It seems that the induction of transplant tolerance in this system is dependent on the presence of CD4+CD25+ regulatory T cells among the recent thymic emigrants. CONCLUSIONS: This study suggests that CD4+CD25+ regulatory T cells specific for the induction of transplant tolerance are similar in origin, phenotype, and function to those involved in the maintenance of self-tolerance and the prevention of autoimmunity.

Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival.

BACKGROUND: Because the differential polarization of T cells in response to antigen presentation is dependent on the maturational state of dendritic cells (DCs), we hypothesized that the adoptive transfer of immature myeloid DCs (iMDCs) would prolong graft survival. METHODS: To evaluate this hypothesis, we studied the effects of transfer of iMDCs and mature myeloid DCs (mMDCs) on rat cardiac allograft survival. RESULTS: Whereas iMDCs that do not express costimulatory molecules induce allogeneic T-cell hyporesponsiveness in coculture studies, mMDCs that express high levels of major histocompatibility complex class II costimulatory and maturation molecules induce a robust allostimulatory T-cell response. Adoptive transfer of Wistar Furth iMDCs, unlike mMDCs, 7 days before cardiac transplantation significantly prolonged graft survival. It was important that adoptive transfer of iMDCs combined with 0.5 mL antilymphocyte serum (ALS) transient immunosuppression on day -7 led to donor-specific permanent graft survival in 50% of recipients. In contrast, adoptive transfer of mMDCs combined with ALS led to graft survival similar to that in recipients treated with ALS alone. Stimulation of CD4 T cells isolated from the spleen of unresponsive allograft recipients with donor antigen resulted in donor-specific hyporesponsiveness and production of interleukin (IL)-10 and transforming growth factor-beta but not IL-4 and interferon-gamma. The tolerant T-cell unresponsiveness was reversed by the addition of IL-2. CONCLUSION: Our data confirming the immunoregulatory effect of immature DCs indicate that induction of transplant tolerance by iMDCs is partly dependent on in vivo generation of regulatory T cells. This finding suggests that immunization with immature donor DCs has therapeutic potential for the induction of transplant tolerance and treatment of autoimmune diseases.

Peritransplant streptavidin recipient treatment prolongs rat cardiac allograft survival.

BACKGROUND: Because streptavidin shows high localization in inflamed tissues, it might also interfere with the proliferation of cells involved in allograft rejection. METHODS AND RESULTS: Treatment of naïve ACI recipients with 20 mg/kg streptavidin i.p. alone significantly prolonged Lewis cardiac allografts from a mean survival time of 9.8+/-0.7 days in controls to 19.8+/-6.5 days, with one recipient accepting the graft permanently (>250 days). Peritransplant streptavidin treatment combined with 0.5 ml of antilymphocyte serum (ALS) transient immunosuppression led to permanent graft survival (>250 days) in 6 of 10 recipients. Second-set skin grafts performed 60 days after the primary cardiac allograft were prolonged to 45 days, whereas the third party Wistar-Furth (WF) skin grafts were rejected in 15 days without the rejection of the primary Lewis cardiac allografts. Pathology of transplanted cardiac allografts at 100 days showed no mononuclear cell infiltration or chronic allograft vasculopathy. Streptavidin given for 5 days at 20 mg/kg caused a moderate initial weight loss but had no effect on hematologic, biochemical, and histologic parameters in the treated recipients. CONCLUSION: This study demonstrates that peritransplant recipient treatment with streptavidin combined with peritransplant ALS induces prolonged cardiac and second-set skin allograft survival. We conclude that recipient peritransplant streptavidin treatment may provide a new strategy for the induction of transplant tolerance.