Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Transplantation. 2009 Oct 15;88(7):879-83. doi: 10.1097/TP.0b013e3181b6efbf.
Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants.
We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.
Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.
These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.
肥胖患者的血浆脂联素水平较低，脂联素是一种具有抗炎和抗动脉粥样硬化特性的脂肪细胞因子，与多种心血管疾病的高发密切相关。本研究探讨了脂联素是否调节主要组织相容性复合体 II 类错配心脏移植中的同种异体移植物排斥反应。
我们将 Bm12 同种异体移植物异位移植到脂联素缺乏（APN-/-，C57BL/6 背景）或野生型（APN+/+）小鼠体内。一些 APN-/-小鼠通过腺病毒接受脂联素重建。组织学分析评估同种异体移植物排斥反应，实时逆转录聚合酶链反应评估与免疫和炎症反应相关的细胞因子/趋化因子基因。此外，我们还测试了脂联素对体外用抗 CD3 抗体刺激的小鼠 T 淋巴细胞增殖和细胞因子/趋化因子产生的影响。
与 APN+/+宿主移植的同种异体移植物相比，移植到 APN-/-小鼠体内的同种异体移植物表现出严重的急性排斥反应，伴有 CD4-和 CD8-阳性 T 淋巴细胞和 Mac3-阳性巨噬细胞的积累增加。APN-/-小鼠中腺病毒提供的脂联素逆转了这些对同种异体移植的加剧反应。APN-/-小鼠的排斥同种异体移植物中肿瘤坏死因子-α、干扰素-γ和调节激活正常 T 表达和推测分泌的水平显著升高。此外，脂联素显著抑制体外用抗 CD3 抗体刺激的小鼠 T 淋巴细胞增殖和产生肿瘤坏死因子-α、干扰素-γ、调节激活正常 T 表达和推测分泌、单核细胞趋化蛋白-1 和干扰素-γ诱导蛋白-10。
这些观察结果为肥胖患者的同种异体移植物受者的免疫调节提供了新的机制见解，肥胖是一种越来越普遍的危险因素。脂联素可能为心脏移植后同种异体移植物排斥反应提供新的治疗靶点。
