由具有显性表位的单一主要组织相容性复合体I类肽诱导的获得性胸腺耐受性机制：淋巴和移植物内区室中调节性细胞因子的差异分析
Mechanism of acquired thymic tolerance induced by a single major histocompatibility complex class I peptide with the dominant epitope: differential analysis of regulatory cytokines in the lymphoid and intragraft compartments.
作者信息
Oluwole S F, Chowdhury N C, Ingram M, Garrovillo M, Jin M X, Agrawal S
机构信息
Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
出版信息
Transplantation. 1999 Aug 15;68(3):418-29. doi: 10.1097/00007890-199908150-00015.
BACKGROUND
We have recently shown that intrathymic injection of a combination of immunogenic WAG-derived or Wistar-Furth (WF) (RT1.Au) major histocompatibility complex class I peptides induces acquired systemic tolerance to cardiac and islet allografts in the WF-to-ACI rat combination and therefore hypothesized that identification of the class I peptide dominance may play an important role in the induction of antigen (Ag)-specific tolerance. This study defined the peptide with the dominant epitope among the seven synthetic RT1.Au peptides and analyzed the immunoregulatory cytokines within the lymphoid and intragraft compartments associated with acquired thymic tolerance.
METHODS
ACI recipients were pretreated with intrathymic (IT) injection of 300 microg of the individual seven RT1.Au peptides 7 days before WF or Lewis cardiac transplantation. Cytokine profile of mixed lymphocyte reaction supernatants of T cells obtained from the thymus, mesenteric lymph nodes, spleen, peripheral blood leukocytes, and graft infiltrating cells after donor (WF) or third-party (Lewis) Ag stimulation were measured by enzyme-linked immunosorbent assay, whereas cytokine gene expression was determined by reverse transcription-polymerase chain reaction.
RESULTS
Only IT injection of peptide 5 (93-109) among the seven RT1.Au peptides induced donor-spe cific tolerance to cardiac allografts in the WF-to-ACI rat combination. In addition, intravenous injection of peptide 5 did not prolong WF graft survival in ACI recipients. Analysis of cytokine production by the tolerant recipients showed significant Ag-specific reduction in the production of interleukin (IL)-2 and interferon-gamma (IFN-gamma) in the thymus, mesenteric lymph nodes, spleen, and peripheral blood leukocytes, which was not associated with a concomitant Ag-specific increase in IL-4 and IL-10 production. Measurement of cytokine mRNA expression confirmed undetectable
背景
我们最近发现，胸腺内注射免疫原性的源自WAG或Wistar-Furth（WF，RT1.Au）的主要组织相容性复合体I类肽的组合，可诱导WF到ACI大鼠组合中对心脏和胰岛同种异体移植物产生获得性全身耐受性，因此推测I类肽优势性的鉴定可能在抗原（Ag）特异性耐受性的诱导中起重要作用。本研究确定了七种合成RT1.Au肽中具有显性表位的肽，并分析了与获得性胸腺耐受性相关的淋巴和移植物内隔室中的免疫调节细胞因子。
方法
在WF或Lewis心脏移植前7天，对ACI受体进行胸腺内（IT）注射300μg七种RT1.Au肽中的每一种进行预处理。通过酶联免疫吸附测定法测量在供体（WF）或第三方（Lewis）Ag刺激后，从胸腺、肠系膜淋巴结、脾脏、外周血白细胞和移植物浸润细胞中获得的T细胞的混合淋巴细胞反应上清液的细胞因子谱，而通过逆转录-聚合酶链反应测定细胞因子基因表达。
结果
在七种RT1.Au肽中，只有肽5（93-109）的IT注射在WF到ACI大鼠组合中诱导了对心脏同种异体移植物的供体特异性耐受性。此外，肽5的静脉注射并未延长ACI受体中WF移植物的存活时间。对耐受性受体的细胞因子产生分析表明，胸腺、肠系膜淋巴结、脾脏和外周血白细胞中白细胞介素（IL）-2和干扰素-γ（IFN-γ）的产生有显著的Ag特异性减少，这与IL-4和IL-10产生的伴随Ag特异性增加无关。细胞因子mRNA表达的测量证实无法检测到
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