Quantitative Studies on Tissue Transplantation Immunity. III. Actively Acquired Tolerance
Quantitative Studies on Tissue Transplantation Immunity. III. Actively Acquired Tolerance
复制标题
组织移植免疫的定量研究。
DOI：
--
复制
发表时间：
1956
期刊：
影响因子：
--
通讯作者：
P. Medawar
中科院分区：
文献类型：
--
作者：
R. Billingham;L. Brent;P. Medawar
“主动获得性耐受”引入免疫学的概念，一个特定的抑制反应。当动物在胎儿时期接触到来自其未来供体的细胞，或来自供体近交系的其他成员的细胞时，组织同种移植物就会产生耐受性（第3.1节）。它取决于(a)胚胎无法通过免疫对抗原作出反应，(b)在以后的生活中继续无法这样做。在小鼠（第3.2、4.1、9节）、大鼠和家兔（第3.4节）以及鸟类（第3.3、5、7节）中诱导耐受性的方法进行了详细描述。在正常的发育过程中，对抗原刺激产生的耐受性反应被敏化或免疫反应所取代。从一种反应模式到另一种反应模式的转变占据了一个“无效期”，在此期间，动物暴露于抗原刺激没有明显的影响。大多数（但不是全部）出生或孵化的小鼠和鸟类已经进入了这个过渡期（第4.1节，第5节）。耐受性是抗原特异性的。当且仅当B中不含a中不含的抗原时（实际上，当a和B是同一高度近交品系的成员时，这一条件最容易满足），在胎儿时期注射了供体a的细胞的动物，在以后的生命中完全耐受来自供体B的同种移植物。耐受动物对来自非亲属供体的同种移植物的反应不会明显受损。然而，耐受性并不能区别于单个个体的组织；用白细胞或乳腺癌细胞接种胎鼠或新生小鼠可能会使其对后来的同种皮肤移植物产生耐受性（第4.2、9节）。同种移植物的耐受性既不是由移植物细胞的抗原适应引起的，也不是由移植物细胞的抗原适应引起的。对身体某一部分的同种移植物能耐受的动物，对身体另一部分也能耐受；耐受性是全身性的，耐受性的移植物不会在其自身的淋巴区域内建立特权地位（第4.3节）。任何程度的耐受性都是可能的，从允许同种移植物仅比正常存活的中位数多活几天，到允许它被宿主永久接受并融入宿主体内。部分抑制反应可能是永久性的，因为在部分耐受的动物中，“二次反应”的减弱与第一次反应的减弱成正比（第3.2节，4.4节）。产生耐受性的刺激物必须是完全抗原的，也就是说，必须是能使年老的动物产生免疫力的刺激物。红细胞等不能引起移植免疫的细胞不能引起组织同种移植物的耐受；所有取消细胞赋予胚胎耐受能力的治疗方法也将取消它们使老年动物免疫的能力（第5条）。免疫反应性可以迅速和永久地恢复到耐受动物，通过接种从其近交系主动免疫成员的局部淋巴结中取出的细胞。它也可以通过接种正常的未免疫的淋巴结细胞来恢复，但速度较慢。因此，耐受小鼠完全保留了产生过继性（“被动”）免疫的能力；耐受的同种移植物仍然是抗原刺激的来源，其对直接针对其的反应的易感性保持不变。耐受性代表了免疫反应机制的核心失效，而不是由外周水平的干预引起的（第6节）。分析了双胞胎、生育能力、耐受性与红细胞嵌合的关系。就像异卵双胞胎牛一样，从双蛋黄鸡蛋中产生的双胞胎小鸡是同步的，是红细胞嵌合体，并且对彼此的皮肤移植具有耐受性。耐受性和不孕症没有因果关系。从胚胎第10天到孵化，人工同步异种共生在雏鸡中产生的耐受性伴随着真正持久的红细胞嵌合。在部分耐受的鸡中嵌合现象的消失并没有显示出正常反应性的恢复，因为它们对通过交叉注射重新引入的红细胞的二次反应严重受损（第7节）。胚胎鸭和雏鸡的同步结合可以达到一定程度的皮肤异种移植的耐受性（第8节）。可通过肿瘤同种移植物产生耐受性，也可通过皮肤的肿瘤同种移植物产生耐受性。一定程度的免疫不足以抑制肿瘤的生长，可能会完全破坏正常的同种移植物；因此，与皮肤同种移植物的存活时间相比，肿瘤同种移植物的生长是一种不那么严格的耐受性衡量标准（第9节）。自然获得的对母体同种移植物的耐受性被认为在豚鼠中很少发生，可能是由于母体细胞意外植入胎儿。在小鼠或家兔中没有观察到这种天然耐受性（第10节）。考虑了与宽容有关的现象。通过给成年动物注射各种修饰的抗原物质而引起的移植免疫的部分抑制与起源模式的耐受性根本不同，因为在给老龄动物注射后促进同种移植物生长的物质没有能力赋予胚胎耐受性，而使胚胎变得耐受性的物质仅仅使成年动物变得免疫（第11.1节）。有人认为，负责移植免疫的同种抗原应该与分化的特殊最终产物有明显区别，后者是同种抗原，因为它们是潜在的自身抗原，而后者是潜在的自身抗原，因为抗体形成系统在正常发育过程中没有机会对它们的作用产生耐受性（11.2节）。容忍现象被认为与哺乳动物母亲和胎儿之间的关系有关；在不同的发育阶段，可能产生对不同抗原的免疫力；根据单个个体不同组织的抗原和遗传组成；以及在正常生活中同种抗原的命运（第11.3节）。
'Actively acquired tolerance' introduces into immunology the concept of a specific inhibition of response. Tolerance of a tissue homograft comes about when an animal has been confronted in foetal life with cells taken from its future donor, or from some other member of the donor's inbred strain (section 3.1). It depends (a) upon an embryo's inability to respond to antigens by becoming immunized, and (b) upon its continued inability to do so in later life. Methods for inducing tolerance in mice (sections 3.2, 4.1, 9), rats and rabbits (section 3.4), and birds (sections 3.3, 5, 7) are described in full. In normal development, response to an antigenic stimulus by becoming tolerant gives way to response by becoming sensitized or immune. The transition from the one modality of response to the other occupies a 'null period' during which the exposure of animals to an antigenic stimulus has no appreciable effect. Most but not all mice and birds at birth or hatching have already entered this transitional period (sections 4.1, 5). Tolerance is antigenically specific. An animal injected in foetal life with cells from a donor A becomes completely tolerant of homografts transplanted in later life from a donor B if, and only if, B contains no antigens that are not also present in A. (In practice, this condition is most easily fulfilled when A and B are members of the same highly inbred strain.) The reaction of a tolerant animal against a homograft from an unrelated donor is not perceptibly impaired. Tolerance does not, however, discriminate between the tissues of a single individual; the inoculation of foetal or newborn mice with leucocytes or with the cells of a mammary carcinoma may confer tolerance of later homografts of skin (sections 4.2, 9). Tolerance of a homograft is neither caused by nor accompanied by an antigenic adaptation of the grafted cells. An animal that is tolerant of a homograft in one part of its body is tolerant in another; tolerance is systemic, and a tolerated graft does not build up a privileged position within its own lymphatic territory (section 4.3). Every degree of tolerance is possible, from that which allows a homograft to live only a few days beyond its normal median expectation of survival to that in which it is permanently accepted by and incorporated into its host. An inhibition of response which is partial may nevertheless be permanent, for the weakening of the 'secondary response' in partially tolerant animals is proportional to the weakening of the first (sections 3.2, 4.4). The stimulus which confers tolerance must be fully antigenic, i.e. must be one which would have caused an older animal to have become immune. Cells such as erythrocytes which have no power to elicit transplantation immunity are incapable of causing tolerance of tissue homografts; all treatments which abolish the power of cells to confer tolerance upon embryos will also abolish their power to make older animals immune (section 5). Immunological reactivity can be promptly and permanently restored to a tolerant animal by inoculating it with cells taken from the regional lymph nodes of actively immunized members of its inbred strain. It may also be restored, more slowly, by the inoculation of normal unimmunized lymph node cells. A tolerant mouse thus retains in full the power to give effect to an immunity of adoptive ('passive') origin; a tolerated homograft continues to be a source of antigenic stimuli, and its susceptibility to a reaction directed against it remains unchanged. Tolerance represents a central failure of the mechanism of the immunological reaction, and is not caused by an intercession at a peripheral level (section 6). The relationship between twinning, fertility, tolerance and red-cell chimerism is analyzed. Like dizygotic twin cattle, twin chicks that arise from double-yolked eggs are synchorial, are red-cell chimeras, and are tolerant of grafts of each other's skin. Tolerance and infertility are not causally connected. The tolerance produced in chicks by artificial synchorial parabiosis from the 10th day of embryonic life until hatching is accompanied by a true persistent red-cell chimerism. The disappearance of chimerism in partially tolerant chickens does not reveal a return to normal reactivity, for their secondary response to red cells reintroduced by cross-injection is profoundly impaired (section 7). Some measure of tolerance of skin heterografts may be achieved by the synchorial union of embryonic ducks and chicks (section 8). Tolerance may be produced by, and in respect of, tumour homografts, and by tumour homografts in respect of skin. A degree of immunity which does not suffice to hold in check the growth of a tumour may destroy a normal homograft completely; the growth of a tumour homograft is therefore a less exacting measure of tolerance than the survival time of a homograft of skin (section 9). A naturally acquired tolerance of maternal homografts is believed to occur, very rarely, in guineapigs, presumably by the accidental incorporation into a foetus of maternal cells. No such natural tolerance has been observed in mice or rabbits (section 10). Phenomena cognate with tolerance are considered. The partial inhibition of transplantation immunity which is caused by injecting adult animals with variously modified antigenic matter differs fundamentally from tolerance in mode of origin, for the substances which enhance the growth of homografts after administration to older animals have no power to confer tolerance upon embryos, and the substances which cause embryos to become tolerant merely cause adults to become immune (section 11.1). It is argued that the iso-antigens responsible for transplantation immunity should be sharply distinguished from those specialized end-products of differentiation which are iso-antigenic because they are potentially auto-antigenic, and which are potentially auto-antigenic because the antibody-forming system has no opportunity in normal development to become tolerant of their action (section 11.2). The phenomenon of tolerance is considered for its bearing upon the relationship between mammalian mother and foetus; upon the different stages of development at which immunity to different antigens may arise; upon the antigenic and genetic composition of the different tissues of a single individual; and upon the fate of iso-antigens in normal life (section 11.3).