dos Santos R R, Rossi M A, Laus J L, Silva J S, Savino W, Mengel J
Evandro Chagas Hospital, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.
J Exp Med. 1992 Jan 1;175(1):29-39. doi: 10.1084/jem.175.1.29.
The contribution of autoimmunity in the genesis of chronic Chagas' heart pathology is not clear. In the present study, we show that: (a) BALB/c mice chronically infected with Trypanosoma cruzi reject syngeneic newborn hearts; (b) in vivo treatment with anti-CD4 but not anti-CD8 monoclonal antibodies (mAbs) abrogates rejection; (c) CD4+ T cells from chronically infected mice proliferate in vitro to syngeneic myocardium antigens and induce heart graft destruction when injected in situ; (d) anti-CD4 treatment of chronically infected mice establishes long-term tolerance to syngeneic heart grafts; and (e) the state of tolerance is related to in vitro and in vivo unresponsiveness of the CD4+ T cells. These findings allow us to suggest that autoimmunity is the major mechanism implicated in the rejection of syngeneic heart tissues grafted into the pinna of the ear of mice chronically infected with T. cruzi. The similarity of the lesions to those found in humans suggests that autoimmunity is involved in the pathogenesis of chagasic cardiomyopathy in humans. Moreover, this could imply therapeutic strategies by reestablishing long-term tissue-specific tolerance with anti-CD4 mAb treatment, mediating anergy, or deleting the responder CD4+ T cells to heart tissue antigens.
自身免疫在慢性恰加斯病心脏病变发生过程中的作用尚不清楚。在本研究中,我们发现:(a) 慢性感染克氏锥虫的BALB/c小鼠排斥同基因新生心脏;(b) 用抗CD4单克隆抗体而非抗CD8单克隆抗体进行体内治疗可消除排斥反应;(c) 来自慢性感染小鼠的CD4+ T细胞在体外对同基因心肌抗原增殖,并在原位注射时诱导心脏移植物破坏;(d) 对慢性感染小鼠进行抗CD4治疗可建立对同基因心脏移植物的长期耐受性;以及(e) 耐受状态与CD4+ T细胞在体外和体内的无反应性有关。这些发现使我们认为,自身免疫是慢性感染克氏锥虫的小鼠耳部移植同基因心脏组织排斥反应的主要机制。这些病变与人类病变的相似性表明,自身免疫参与了人类恰加斯病心肌病的发病机制。此外,这可能意味着通过用抗CD4单克隆抗体治疗重建长期组织特异性耐受性、介导无反应性或清除对心脏组织抗原产生反应的CD4+ T细胞来制定治疗策略。