Biomedical subjects

Christian S Hinrichs

Publications and source records attributed to Christian S Hinrichs.

8 recordsLinked to original sources

PubMed2006

Interleukin-2-dependent mechanisms of tolerance and immunity in vivo.

IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of T(reg) cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for T(reg) cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2(-/-) and CD25(-/-) mice both contained Foxp3(+) T cells in the periphery. IL-2R signaling was also important for CD8(+) T cell immunity, because CD25(-/-) tumor-reactive CD8(+) T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor/self-Ag in vivo.

Animals↗

PubMed2006

Programming CD8+ T cells for effective immunotherapy.

The differentiation state of CD8+ T cells has emerged as a crucial determinant of their ability to respond to tumor and infection. Signals from T-cell receptors, co-stimulatory molecules and cytokine receptors direct the differentiation process. These signals 'program' sustained and heritable gene expression patterns that govern progressive differentiation and lineage commitment. The epigenetic mechanisms by which T cells are programmed are just beginning to be elucidated. Understanding the mechanisms that control CD8+ T-cell differentiation is important in the development of novel immunotherapy strategies.

Animals↗

PubMed2005

Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor gamma chain (gamma(c)), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-gamma production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R-/- mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Animals↗

PubMed2004

Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer.

Immunotherapy using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8+ T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans.

Adoptive Transfer↗

PubMed2004

The effectiveness of complete decongestive physiotherapy for the treatment of lymphedema following groin dissection for melanoma.

OBJECTIVE: Groin dissection is performed for the treatment of melanoma and other malignancies. Lymphedema rates as high as 47% have been reported. In 1996, we began using complete decongestive physiotherapy (CDP) in selected patients with lymphedema following groin dissection. Here, we review our results in a small cohort of patients. METHODS: A retrospective review of the medical records of 14 patients, treated with CDP for lymphedema secondary to groin dissection for melanoma was conducted. All patients were treated with CDP at Roswell Park Cancer Institute (RPCI), between 1996 and 2002. Of the 14 patients, 12 underwent groin dissection at RPCI. Response to therapy was measured by limb volume determinations. Patient gender, age, body mass index (BMI), type of operation, type of adjuvant therapy, time to treatment, patient compliance, lymphedema stage, and initial edema were analyzed for association with response to treatment. Incidence was estimated by a review of the operative logs. RESULTS: Fourteen patients were treated with CDP for lymphedema secondary to groin dissection for melanoma, with a median decrease in lymphedema of 60% (range: 35-145%; P = 0.0003). Increased BMI was associated with a decreased response to treatment (P = 0.02). Response to CDP was not effected by time to treatment, patient compliance, lymphedema stage, and initial edema. During this time, 39 groin dissections were done at RPCI. The incidence of lymphedema treated with CDP at RPCI was 31% (12/39; standard error 7.4%). CONCLUSIONS: With a decrease in lymphedema of 60%, CDP may provide relief for patients with lymphedema following groin dissection. Elevated BMI was associated with a decreased response to CDP.

Adult↗

PubMed2004

Lymphedema secondary to postmastectomy radiation: incidence and risk factors.

BACKGROUND: Postmastectomy radiotherapy (PMRT) has proven benefits for certain patients with breast cancer; however, one of its complications is lymphedema. This study examines the incidence of and risk factors associated with lymphedema secondary to PMRT. METHODS: The charts of patients treated with mastectomy at Roswell Park Cancer Institute between January 1, 1995, and April 20, 2001, who received PMRT were reviewed. Univariate analysis of patient, disease, and treatment variables was conducted. Multivariate analysis was performed on variables found to be significant in univariate analysis. RESULTS: One hundred five patients received PMRT. The incidence of lymphedema was 27%. Patient age, body mass index, disease stage, positive lymph nodes, nodes resected, postoperative infection, duration of drainage, chemotherapy, and hormonal therapy were not associated with lymphedema. Total dose (P =.032), posterior axillary boost (P =.047), overlap technique (P =.037), radiotherapy before 1999 (P =.028), and radiotherapy at Roswell Park Cancer Institute (P =.028) were significantly associated with lymphedema. Increased lymphedema was noted with supraclavicular, internal mammary, mastectomy scar boost, and chest wall tangential photon beam radiation, but the associations were not statistically significant. CONCLUSIONS: The high incidence and debilitating effects of lymphedema must be weighed against the benefits of PMRT. Efforts to prevent lymphedema should be emphasized.

Breast Neoplasms↗

PubMedDate not supplied

Esophageal cancer.

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Journal Article↗

PubMedDate not supplied

Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells.

Glucocorticoids are potent immunosuppressive drugs that are generally withheld from cancer patients receiving immunotherapy. We sought to test the hypothesis that glucocorticoids might interfere with the function of cells after adoptive transfer. We gave dexamethasone, a potent synthetic glucocorticoid, to B16 melanoma-bearing mice receiving the adoptive cell transfer (ACT) of pmel-1 T-cell receptor transgenic CD8+ cells. Dexamethasone caused a profound lymphodepletion but, surprisingly, did not alter the antitumor efficacy of ACT-based regimens whether given before, during, or after ACT. Although dexamethasone radically decreased the number of native CD8+ splenocytes in recipient mice, it did not affect the numbers of CD8+ pmel-1 cells derived from ACT in these mice. In vitro proliferation assays revealed acute inhibition of naive pmel-1 CD8+ cells by dexamethasone without significant effect on activated cells. In vitro interferon (IFN)-gamma release from activated pmel-1 CD8+ cells showed partial inhibition by dexamethasone, but this effect was relatively minor when compared with the near-complete inhibition of naive cells. Thus, glucocorticoids had a profound inhibitory effect on naive CD8+ T cells but had little impact on the proliferation and function of activated CD8+ pmel-1 T cells. Finally, because glucocorticoids had no effect on tumor regression in this model, it may be possible to use glucocorticoids in some patients receiving ACT-based immunotherapy regimens.

Animals↗