Immune response: Tissue specific T-lymphocytes

Medical Hypotheses MtdiLnlHypotheses (1992)37,76-84 0 Longman Group UK Ltd 1992

Immune Response: Tissue Specific T-Lymphocytes

B. DAUNTER

The University of Queensland, Department of Obstetrics and Gynaecology, Clinical Sciences Building, Royal Brisbane Hospital, Herston, Queensland Q 4029, Australia

Abstract - The lymphatic system forms a ‘blind’ plexus of vessels that in general are found in tissue which has an inherently high replicative capacity. It is this system that is responsible for the rapid deployment and circulation of tissue-specific T-lymphocytes for the inspection of cell-surface aberrations within the tissue. The presence of tissue-specific T-lymphocytes explains why 90% of lymphocytes are found outside the lymphatic system and why they migrate in a selective manner. The tissue-specific T-lymphocyte is considered to express a common lymphocyte cell surface pattern, the homotype, and a tissue-specific cell-surface pattern, the histotype which may involve MHCA and mHCA. It is the histotypic pattern that is responsible for the tissue specificity of the tissue-specific T-lymphocyte. The presence of tissue-specific T-lymphocytes does pose problems for the immune system. If different tissue-specific T-lymphocytes met within a particular tissue, ‘lost’ lymphocytes, an immune response will be generated against the intruder (lost lymphocyte), and the intruder will not be able to recruit other immunocompetent cells in that tissue. This immune reaction is an attempt to change the histotypic pattern of the intruder. This situation would explain the autologous immune response. This response however is suppressed in the systemic system by immunosuppressive compounds from the liver. It is only in the tissues that the tissue-specific T-lymphocytes are released from this suppression, in order to initiate immune reactions against aberrant cell-surface patterns.

Introduction

The concept of tissue-specific T-lymphocytes was first published in 1979 (1) under the title of the Reversal Immune Surveillance Hypothesis (RISH). RISH tissue-specific T-lymphocytes (Tts) respond to aberrations in the plasma membranes of the cells they are inspecting. This involves the transfer of cell surface DNA from the aberrant cell to the Tts which undergoes blastogenesis to give rise to a dual

functional T-helper/suppressor cell (T p/y, T ccly or T E/y) and a B-lymphocyte. The B-lymphocyte contains the transferred DNA along with a portion of the Tts DNA. Under the control of the T-helper/ suppressor cell, the B-lymphocyte becomes a plasma cell or a memory cell capable of secreting immunoglobulin. The variable region of the immunoglobulin being derived from the activation of the DNA complementary to the transferred aberrant DNA. B-lymphocytes not induced to

76

IMMUNE RESPONSE: TISSUE SP!ZCFIC T-LYMPHOCYTES 77

become plasma cells can later be recruited. along with memory cells from the lymph nodes by antigen specific T-helper/suppressor cells. Thus the primary immune response occurs in the tissues and the secondary or memory response is generated in the lymph nodes (2-7).

Lymphatic system

If lymphocytes are involved in monitoring cell surface patterns, then they must be widely distributed throughout the body, and be highly motile. The distribution of lymphocytes throughout the body is performed by the lymphatic system, whereas phagocytes are distributed to tissues mainly by the systemic circulation. The lymphatic vessels arc found in the connective tissue of the body and form a plexus of ‘blind’ lymphatic capillaries next to the most superficial layer of blood capillaries (8). Therefore, the lymphatic system is almost as extensive in its distribution as the systemic circulatory system, almost as extensive, because not only are lymphatic vessels absent in avascular tissues such as hyaline cartilage and the cornea, but they are also absent from some vascular tissue such as the brain, spinal cord and the globe of the eye (8). This is interesting, because in general, it is only those tissues with an inherently high replicative capacity that are invested with a rich plexus of lymphatic vessels. The lymphatic system therefore allows rapid distribution of lymphocytes to those tissues whose cells may undergo a dysfunctional cell surface change. This does not imply that the absence of lymphatics to a particular tissue means the absence of tissue-specific T-lymphocytes. It is a matter of degree in the necessity for the distribution of lymphocytes based on the replicability of the various tissues. Even in tissue, such as the brain, which does not have a lymphatic systemper se. the blood vessels entering the brain and spinal cord are surrounded by perivascular spaces, which may play the part of lymph vessels (8). The ramifications of the lymphatic system explains why 1300 g of lymphocytes are distributed throughout various tissues, excluding the systemic circulation, which contains 3 g, the bone marrow 70 g, and the lymphatic tissue 100 g (9). It would appear therefore that we need to examine the function of the lymphocytes in the various non-lymphoid tissues, that is at their place of ‘work’, rather than on their way to or from ‘work’ in the systemic

circulation and lymphatics, which together only contain approximately l/lOth of the total lymphocyte population.

There is a continual recycling of lymphocytes from the various tissues to lymphoid tissues such as the lymph nodes and Peyer’s patches. This recycling of lymphocytes is a rapid process, as demonstrated in the sheep in which it was calculated, that 30 x lo6 lymphocytes per hour pass in the efferent lymph from a lymph node weighing 1 g (10). Hence, an equilibrating pool of circulating lymphocytes is maintained. When one examines the lymphatic system, it is seen that by tracing the lymphatic vessel back from its terminal ‘blind’ end, a lymph node is encountered. The distribution of these vessels and uodes gives the impression of a local circulatory system from which lymphocytes move out into the surrounding tissue. Lymphocytes move out from this system to bring information back for processing in the local lymph nodes. In this respect, we do not differ from the accepted view of the immune response, i.e. (i) the sensitization or afferent phase can be in-

itiated outside the lymphatic system by contact between lymphocytes and the immunogen (1 I, 12);

(ii) the draining lymph nodes in the area where sensitization occurs enlarge due to lymphocyte replication and differentiation into effector, memory and suppressor lymphocytes (13-15);

(iii) the effector lymphocytes move from the lymph node to mediate the immune response (16-18), and

(iv) memory of the immune stimulation is re- tamed, resulting in an accelerated response on secondary exposure to the immunogen (13,16, 19).

However, since we are considering T-lymphocytes to be tissue-specific, the afferent and efferent (effector) T-lymphocytes are one of the same, as opposed to two separate populations (20). The difference between these same tissue-specific T-lymphocytes is that one is sensitized (afferent) and the other becomes sensitized (efferent) by afferent T-lymphocyte recruitment. Until such recruitment of ‘efferent’ lymphocytes by afferent lymphocytes occurs, it should be, and is possible, to distinguish between the two types of lymphocytes. That is, one is sensitized (afferent) and the other is not (efferent). When the tissue-specific T-lymphocytes move out from their local lymph nodes into the surrounding tissue, they will be held in that

78 MEDICAL HYF’O’I-HESES

testicular cells into the peritoneal cavity (23). Similarly, lymphocyte rosetting formation has been found to occur with normal and neoplastic murine Leydig cells (24, 25). This autologous rosetting with lymphocytes also displays some species specificity (26). Thus, the necessity for recognition of communicatiou between autologous cells of the immune system may explain rosette formation between T-cells and macrophages (27) and lymphocyte/lymphocyte rosette formation (28). Indirectevidence for tissue-specific T-lymphocytes has also been demonstrated by the binding of certain rat thoracic duct lymphocyte populations to glutaraldehyde-fixed tissue of cerebellum and cerebrum. There was preferential binding of lymphocytes to myelinated area which was quantitatively similar at the sites of lymphocyte adherence (29). This type of adherence or binding may not occur so avidly in vivo, particularly when we consider that glutaraldehyde may aggregate cell surface receptors, and that optimum binding in this experiment took place at 7°C. The lymphocytes from the thoracic duct showed less or little adherence to glutaraldehyde-fixed tissue sections of the liver, spleen, heart, thymus and salivary glands (29). This finding may simply be the result of lymphocyte sampling. To reiterate, we need to recover lymphocytes from various tissues and examine their reactivity with that tissue. If we take peripheral blood or thoracic duct lymphocytes for the analysis of cellular interaction with other cells, or for the analysis of lymphocyte cell surface components, the results will be heterogeneous.

The labelling of human T-lymphocytes with radioactive sodium borohydrlde and subsequent isolation of the radioactive components has shown that the glycoprotein pattern of T-lymphocytes is different from that of other haematopoietic cell lines (30). Antisera to human T-lymphocyte membranes and affinity chromatography using lectins has also been used to distinguish T-lymphocyte specific glycoproteins (3 1). Similarly, B-lymphocyte specific antigens have also been identified (32).

tissue by association and dissociation with the cells of that tissue. These T-lymphocytes wilI eventually leave the tissue and enter the blood vessels or the lymphatics in that area and move back into the local lymphatic system for recirculation. Therefore we have a local circulation of lymphocytes.

Tissue-specific T-lymphocytes

Lymphocytes do possess the capacity to migrate in a selective manner. They are seen to enter certain tissues more readily than other leucocytes and migrate to lymphoid tissues at specific sites. This is further supported by the fact that subsets of lymphocytes from different tissues show specific statistically-derived patterns of migration in relation to certain lymph nodes and to the spleen (21). For lymphocytes to inspect cells in a given tissue, they would need to be highly motile, which they are. However, some lymphocytes become even more motile upon immune stimulation in vivo or in vitro (22). Murine lymphocytes in vitro have been observed to crawl over fibroblasts at speeds of up to 20 pm/m@ the lymphocytes, which were predominantly T-lymphocytes were observed to crawl ‘on top of, along the edges of, and preferentially beneath the attached fibroblasts’. Surface contact between the cells was observed and sometimes this contact involved fine cellular T-lymphocyte processes. The intensity of the crawling activity was correlated with the intensity of homologous antigenic stimulation in vivo. This crawling activity of the T-lymphocytes did not appear to depend upon autologous or allogeneic histocompatibility antigens (HCA). This T-lymphocyte activity was rarely displayed by those lymphocytes fromthe thymus or spleen, which may be due to lack of maturity and/or lack of activation. The fibroblasts used in this experiment were established 3T3 and transformed L cells. It is possible that these cells may have undergone cell surface modulation relative to their original state before culture. Thus the true relationship between the lymphocytes and the fibroblasts may not be apparent. However, the experiment does demonstrate the basic crawling phenomenon of T-lymphocytes, as if engaged in cell surface exploration. Similarly, the spontaneous adherence, that is, rosette formation between cells also suggests self-recognition.

Rosetting of murine Leydig cells and lymphocytes occurs after the injection of autologous

RISH tissue-specific T-lymphocytes

Tissue-specific T-lymphocytes, and indeed all cells of the reticuloendothelial system will have a homotypic, embryotypic, allotypic (MHCA) and idiotypic (mHCA) cell surface pattern (33). However, these cells do not associate with like cells to form three dimensional structures culminating in

IMMUNE RESPONSE: TISSUE SPECIFIC T-LYMPHOCYTES

a functional organ. This suggests that these cells do not carry the basic mechanisms to form permanent or semi-permanent associations between like-cells. In addition, if the T-lymphocytes are tissue- specific, they must carry elements common to the cells they are inspecting. This may be explained by a reduction in the T-lymphocytes’ homotypic pattern in order to accommodate elements of the homotypic pattern of another tissue - the T- lymphocyte histotype (Fig. 1).

An immune response will be initiated between two different tissue-specific T-lymphocytes because of the difference in conformation between - (i) histotypic/allotypic, and (ii) histotypic/ idiotypic patterns. Similarly, any conformational change between (i) homotypic/allotypic, (ii) homotypic/idiotypic, and (iii) homotypic/ histotypic/embryotypic patterns will also induce an immune response against the tissue-specific T-lymphocyte.

The evidence for the presence of other tissue antigens (histotype) on T-lymphocytes which, according to RISH specific tissue-specific T-lymphocytes is not so well defined as that of specific T-lymphocyte glycoproteins (homotype). We must remember that such analysis is based on whole populations of T-lymphocytes. Tissue specificity has not been considered. Also, some of the components that have been detected on T-lymphocytes may be common to tissue of the same embryonic origin. These may be structural components or receptors, such as receptors for insulin or some other hormone. For example, it has been shown that an antigen 4F2 defined by monoclonal antibody is present on monocytes and on 70% of lectin or allogeneic-activated T-lymphocytes, and on a number of cell lines (34). The monoclonal antibody FlO-89-4 has identified an antigen on human spleen, lymph node, chronic lymphatic leukemia cells, bone marrow, thymus andgranulocytes, but it is absent from brain, kidney, liver, heart, erythrocytes, platelets and normal serum (21). Further analysis showed all thymocytes, lymph node lymphocytes, blood mono- nuclear cells and granulocytes were carrying this antigen, FlO-89-4, but heterogeneity in positivity for this antigen was observed (35). The problem is that we are not in search of a particular antigen. We also need to define the function of such antigens precisely. In addition, when we use antisera to identify lymphocytes, this antiserum will cause perturbation of the cell membrane, and may initiate changes and expression of antigens that may not

79

Fig. 1 Diagrematic representation of the surface of tissue- specificT-lymphocytes.

occur in vivo. The use of xenogeneic antisera has however established that the cell surface of human lymphocytes is distinct from that of other tissue, and can express antigens representative of other tissue. This has been demonstrated for a number of human placenta-derived glycoprotein antigens. Common subunit antigens expressed by other cells were found not to be expressed by lymphocytes, whereas other placental antigens were (36). These placental antigens do not appear to be HLA, enzymes or transport glycoproteins, and may be placental identification antigens of the homotype. Similarly, the mouse antigen now called Thy-l was identified on murine lymphocytes in two allelic forms: Thy-l.1 (OAKR) and Thy-l.2 (0-C3H). Thy-l.1 is found in large amounts on mouse and rat thymocytes and brain, and in small amounts on mature T-lymphocytes, whereas the Thy-l .2 appears specific for the mouse (37). There also appears to be lymphocyte surface antigens that resemble HLA antigens. Three such antigens have been isolated from the leukaemic T-lymphocyte line, MOLT-4, and one antigen is recognized by two monoclonal antibodies 0KT6 and NAIf34 (30). The second antigen is defined by monoclonal antibody OKTlO and is found on all T- and B-cell lines. The third antigen is distinct from the other two and is found on some T-cell lines and is absent from other haematopoietic cell lines (38). The interesting fact here is the close resemblance of two of the antigens with HLA antigens. There may well be a serological graduation of serologically-like

80 MEDICAL HYPOTHESES

antigens into distinct tissue-specific antigens forming the homotypic, embryotypic and histotypic patterns.

If T-lymphocytes are tissue-specific, and inspect cell surfaces in order to detect a dysfunction in that cell surface, then T-lymphocytes must also inspect other T-lymphocyte cell surfaces. This also applies to the inspection of B-lymphocytes and macrophages by T-lymphocytes not only to detect a dysfunction in the cell surface pattern, but also in order to generate an immune response. In fact, interactions between T-lymphocytes, B-lymphocytes and macrophages by direct cell contact are required for the generation of an immune response, and this is dependent on compatibility for the MHCA. It has been established that for T-lymphocytes to cause lysis (cytotoxic T-lymphocyte lysis - CTL) of a target cell, they both must be compatible. In the mouse, this compatibility resides in the H-2K or D loci, and in the human at the HLA-A and/or B loci. T-lymphocyte co-operation with B-lymphocytes in antibody synthesis, the activation of and presentation of antigen by macrophages and delayed-type hypersensitivity is dependent in the mouse on compatibility or recognition at the H-21 region, and in the human at the HLA-D region (39-45). Therefore, in the case of the CTL, how do they recognise allogeneic HLA antigen target cells? The fact that l-10% of T-lymphocytes in any individual is reactive to any allogeaeic HLA (46) is no explanation, but merely an observation (see 47).

Tissue-specific T-lymphocytes: homing

The homing of tissue-specific T-lymphocytes to and from the lymphatic system must either identify a chemotactic substance or a membrane component in the blood-tissue barrier. The former is not conceptually attractive because of the obvious difficulties in maintaining a constant chemotactic gradient. The latter, a membrane component in the blood-tissue barrier, may be acceptable. This is because one theory for the formation of lymphatic vessels is that they are formed initially as lymphatic sacs from the outgrowths of veins (8). If these physical connections are maintained between the lymphatic vessels and the blood vessels, for example, by intercellular processes and/or by membrane components, a ‘hybrid’ membrane recognition pattern will be formed. The T-lymphocytes may then be able to identify the

point at which to enter or leave the lymph/blood system which they would encounter in their own local circulatory system. Similarly, this would apply to B-lymphocytes. This situation may explain the in vitro demonstration of rat tboracic duct lymphocytes selectively adhering to specialized post-capillary venule endothelial cells, when the endothelial binding sites are aggregated with cross-linking reagents (48). This has recently been reviewed (1989), (49-52), and the conclusion 10 years after the first publication of RISH (1) was in agreement in that it constitutes a tissue-specific recognition system.

It therefore follows that the lymphocytes must be tissue-specific. The tissue specific T-lymphocytes, on contact with the endothelial cells may induce aggregation of the endothelial cell receptors, resulting in binding and transport of the lymphocytes. Earlier studies on the movement of lymphocytes from the blood to the lymph nodes (homing) in the mouse (53) and rat (54) implicated the involvement of HCA. More definitive studies in the mouse have shown that the homing of lymphocytes labelled with radioactive sodium chromate is dependent on histocompatibility between the donor and recipient of the labelled lymphocytes (55). It was shown that no homing would occur in the case of complete disparity at the H-2 complex but optimal homing was observed with identity at the the H-2 complex (55). In recombinant experiments, it was shown that a single H-2K and/or H-2D compatibility allowed almost optimal homing (55). Almost optimal homing suggests that other HCA antigens may also be involved - mHCA.

Tissue-specific T-lymphocytes: circulation

The lymphatic system is not closed as in the venous system in the transport of blood. Thus, some tissue- specific T-lymphocytes may be transported to other local lymph nodes of other tissue. When these T-lymphocytes leave the lymphatic system, it is possible that as they enter the ‘foreign’ tissue, they move quickly through the tissue aad back to the lymphatics. This is because there will be no association with the surrounding tissue. This may explain part of the spleen’s function in that it is the major site of lymphocyte recirculation, and as such, carries and directs traffic several times that of other lymphoid tissue (56). Eventually, the tissue- specific T-lymphocytes would be transported to the

IMhWNE RESPONSE: TISSUE SPECIFIC T-LYMPHOCYTES

correct tissue, purely on a statistical distribution basis. This is possible when one considers the rapidity in the transport of lymphocytes as discussed previously. Once the ‘lost’ tissue-specific T-lymphocytes are ‘returned home’, they will tend to stay within that tissue and local lymph system because of their tissue-specificity, by association with the cells they are inspecting. Therefore, within any organ there will be a majorpopulation of tissue- specific T-lymphocytes and small populations of other T-lymphocytes not specific for that tissue - the ‘lost’ lymphocytes. However, the ‘lost’ lymphocytes may undergo tissue-specificmodulation, and take on the characteristics required to monitor the tissue in which they are found. This change in lymphocyte tissue-specificity may require an immune response on the part of the resident lymphocytes which will depend upon the duration of residence of the ‘lost’ lymphocytes (2,4). This will involve recruitment of local B-lymphocytes and tissue-specific T-lymphocytes. The ‘lost’ or changed T-lymphocytes would be unable to recruit the local tissue-specific T-lymphocytes, because they have different tissue-specificity and would be unto-operative. Of course, it is debatable whether or not the ‘lost’ T-lymphocyte will be in that locality for a sufficient duration to induce an immune response. However, this situation may explain, in part, the occurrence of antilymphocyte antibodies in healthy individuals (57-59), as well as an immune response, to facilitate the removal of aged or changed lymphocytes from the circulation, Therefore, B-lymphocytes and T-lymphocytes are self-autoreactive, and would explain the autologous immune response (60).

The B-lymphocyte would be recruited from the local lymph nodes by the tissue-specific T-lymphocytes and pass via the local circulation to the tissue. The recruitment of B-lymphocytes by T-lymphocytes in lymph nodes has been indicated by the use of monoclonal antibodies. In the lymph nodes, the T-lymphocytes tend to occupy the paracortical areas, whereas B-lymphocytes tend to occupy the follicular areas. The monoclonal antibodies Tl and T3 which define all mature peripheral T-lymphocytes, were found to be reactive with the majority of lymphocytes in the paracortical region of the lymph nodes. The majority of lymphocytes in the primary follicles were reactive with anti-Ia and anti-IgM, B-lymphocytes (61). A substantial number of lymphocytes of the capsular side germinal centres of secondary follicles were Tl+ and T3+. The

81

majority of Tit and T3+ lymphocytes in both the paracortex and follicles were T4+. which defines inducer/helper lymphocytes (61). A minority of the lymphocytes in these areas were T5+ and T8+, which defines cytotoxic/suppressor lymphocytes. No reaction was found with anti-T6 which defines thymocytes (61). These results demonstrate that the lymph node T-lymphocyte are mature and active, and may be involved in B-lymphocyte recruitment. The B-lymphocytes would then pass via the local lymphatic circulation to the tissue. The passage of the B-lymphocytes through the tissues may be rather passive, since they do not appear to perform cell inspection (22) by association and dissociation with other cells. In addition, T-lymphocytes may also recruit B-lymphocytes that are already in the tissue. The distribution of B-lymphocytes may be subjected to the effects of an open system and associate or be stimulated by the antigen for which they are specific.

The presence of self-reactive cytotoxic T-lymphocytes has been demonstrated in murine lymphocytic choriomeningitis (62), and autoreactivity appears to be regulated by suppressor and autotoxic lymphocytes (63). The pre-requisite for the demonstration of autoreactive T-cells is lymphocyte blastogenesis (64-67). This has been shown to occur with normal murine splenocytes (63), in murine viral infection (62) and in old or cyclophosphamide-treated mice (64-66). However, we must be careful how we interpret such results. Firstly, there is the uormal level of self-reactivity in terms of aged and ‘lost’ lymphocytes by which autoreactivity per se of normal murine splenocytes (63, 66) may be explained. In addition, however, those experiments involving virus-infected cells (62) and cyclophosphamide-treatedmice (64,65) in the induction of self-reactive T-lymphocytes would be the result of changed T-lymphocyte antigenicity (change in cell surface pattern). Thus, the immune response passes from the realm of immunobiology to immunopathology, resulting in the destruction of the treated cells. More recently, polyclonally- activated splenic lymphocytes transferred to syngeneic or autologous mice were shown to produce a local lymph node response. When given intravenously, splenomegaly resulted. These responses were similar to that using allogeneic splenocytes (67). The immune response to the polyclonally-activated lymphocytes could not be attributed to virus infection or mitogen used to activate the lymphocytes (67). This in vivo immune response was also demonstrated in vitro in a

82

one-way synergistic mixed lymphocyte culture reaction (SMLC), mediated by T-lymphocytes (68) with the capacity of immune memory (69). These results demonstrate that self-reactive T-lymphocytes are present in heterogeneous populations of polyclonally-activated T-lymphocytes. This reactivity may be directed against their different tissue specific patterns and may be considered as a heterogeneous group of ‘lost’ tissue-specific T-lymphocytes. Presumably, such reactions do not occur in the spleen or thymus which may be controlled by thymic hormones (70). But what happens in the systemic circulation when these lymphocytes meet? It is known that normal mouse or rat serum will suppress autosensitization and proliferation of autoreactive T-lymphocytes in vitro (71), but not allogeneic responses (72). This may be the result of thymic hormone influence and the regulation of self-recognition by the thymus. In addition, or alternatively, the action of suppressor lymphocytes and/or macrophages may be involved. But there is another possible non-specific immune regulatory system-the liver.

It has been shown that a liver allograft in the pig will survive for a few months, whereas renal, heart or skin allografts survive for a few days. Saline extracts of pigs’ liver, but not spleen, appear to contain a non-toxic compound or compounds that can suppress the blastogenic response of pig lymphocytes to various plant mitogens (73). It has not been established whether or not this compound is active in vivo as it is in vitro. If it is not active in vivo, then an alternative explanation for the pro- longed survival of the pig liver allograft is required. Although one could evoke other more specific immunosuppressive systems to explain the retention of the liver allograft in the pig, non-specific immunosuppression by the liver has an intrinsic appeal. Therefore, the liver may ‘damp’ the immunoreactivity of these lymphocytes, which pass through it, and/or the compounds causing the immunosuppression may be limited to the systemic circulation by virtue of their molecular size. In this case, lymphocytes would have limited immunoreactivity in the systemic circulation and would be released from this control in the lymphatic system, and in the tissues. This makes biological economic sense, in that the lymphocytes would be completely active attheirplace of ‘work’. Thismay explain why the uptake of tritiated [31-I]-thymidine by peripheral blood lymphocytes is increased if they are washed a few times before culture, especially those from cancer patients (74).

MtD1cAL I-IwOTIiEsES

References

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Daunter B, Mackay EV. The reversal immune surveillance hvnothesis (RISH). Med Hvwth Xl 1)~ 207.1979.

Da&r B, Mackay EV. RISH II. h4ed Hyp& 7(5): 555, 1981.

Daunter B. RISH III. Haplotype-sharing in immune mspon- ses. Med Hypoth 17: 79, 1985. Daunter B. RISH IV. Immunoglobulin diversity. Med Hypoth 17: 197,1985.

Daunter B. RISH V. Application to monoclonal antibody production. Med Hypoth 17: 337,1985.

Daunter B. RISH VI. General evolutionary aspects of the immune system. Med Hypoth 27: 115.1988

Daunter B. RISH VII. Cell surface patterns - association of like cells. Med Hypoth 27: 127,1988.

Garven HSD. A Student’s Histology. E & S Livingstone Ltd, p 262, 1965.

Pulvertaft RI. Cellular associations in normal and abnormal lymphocytes. Proc R Sot Med 52(5): 315,1959.

Hall JG. Quantitative aspects of the recirculation of lymphocytes: an analysis of data from experiments on sheep. J Exp Physiol52: 761967.

Medawar PB. The homograft reaction. Pmc R Sot Lond (Biol) 149: 145, 1958.

12. Turk JL. Lymphocyte mspome to antigens A. Affetent side

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

of sensitization arc. Response of lymphocytes to antigens. Transplantation S(Suppl): 952,1967.

Mitchison NA. Studies on the immunological response to foreign tumour transplants in mousy role of lymph node cells in conferring immunity by adoptive transfer. J Exp Med 102: 157,1955. Stark RB, Dwyer EN, DeForest M. Effects of surgical ablation of regional lymph nodes on survival of skin homografts. Ann NY Acad Sci 87: 140,196O.

Billingham RE.. Silvers WK. Wilson DB. Further studies on adoptive transferofsensitivity to skin homografts. J Exp Med 118(3): 397.1963.

Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity; origin, strength and duration of actively and adoptively acquired immunity. Proc R See Lond 143: 58,1954. Hall JG. Studies of the cells in the tierent and effemnt lymph of lymph nodes draining the site of skin homografts. J Exp Med 125(5): 737.1967.

Pederson NC, Morris B. The role of the lymphatic system in the rejection of homogmfts: a study of lymph from renal transplants. J Exp Med 131(5): 936,197O.

Gowans JL, Uhr JW. The carriage of immunological memory by small lymphocytes in the rat. J Exp Med 124(5): 1017,1966.

Cohen IR, Livnat S. The cell-mediated immune response: interactions of initiator and recruited T lymphocytes. Transplant Rev 29: 24,1976.

Morris B. The homing of lymphocytes. Blood Cells 6(l): 3,198O. Chang TW, Celis E, Eisen HN, Solomon F. Crawling movements of lymphocytes on and beneath fibroblasts in culture. Proc Nat1 Acad Sci USA 76(6): 2917, 1979.

Rivenson A. Rosettes lymphocytaims des cellules in tenti- telles testicularires de souris. CR Sot BioI (Paris) 166: 1417,1976.

Rivenson A, Madden RE. Leydig tumour-cell rosettes. N Engl J Med 294(l): 49, 1976.

IMMUNE RESPONSE: TISSUE SPEClFIC T-LYMPHOCYTES

30.

31.

32.

33.

34.

25. Born W, Wekerle H. Selective immunologically non-spe-

29. Kuttner BJ, Woodruff JJ. Selective adherence of lympho-

cific adherence of lymphoid and myeloid cells to Leydig

cytes to myelinated areas of rat brain. J Immunol~l22(5):

cells. Eur J Cell Biol26(1): 76, 1981.

1666,197Q.

26. Galih U. Galili N, Vanky F, Klein E.

Andersson LC, Gahmberg CG, Nilsson K, Wigzell H. Sur- face glycoprotein patterns of normal and malignant human

Natural species-restricted attachment of human and murine T lymphocytes to

lymphoid cells. I. T cells, T blasts and leukemic T cell

various cells. Pmc Natl Acad Sci USA 75(S): 2396,1978.

lines. Int J Cancer 20(5): 702,1977.

27. Siegel I. Natural and antibody-induced adherence of guinea

Pratt DM, Schlossman SF, Sttominger JL. Human T lym-

pig phagocytic cells to autologous and heterologous thymo-

phocyte surface antigens: partial purification and charac-

cytes. J Immunol lOS(4): 879, 1970.

terization utilizing a high titer heteroantisemm. J Immunol

28. Kolb H, Kriese A, Kolb-Bachofen V, Kolb HA. Possible

124(3): 1449,198O. Tada N, Kimum S, Hoffmann M, Hammerhng U. A new

mechanism of entrapment of neuraminidase-treated lym-

surface antigen (PC.2) expressed exclusively on plasma cells. Immunogenetics I l(4): 35 1, 1980.

Daunter B. RISH VII. Cell surface patterns - association

ohocvtes in the liver. Cell Immuno140(2): 457. 1978.

of like cells. Med Hypoth 27: 127,1988. Haynes BF, Hemler ME, Mann DL, et al. Characterization of a monoclonal antibody (4F2) that binds to human monocytes and to a subset of activated lymphocytes. J Immunol 126(4): 1409,198l.

Dalchau R, Kirkley J, Fabre JW. Monoclonal antibody to a human leukocyte-specific membrane glycoprotein prob- ably homologous to the leukocyte-common (L-C) antigen of therat. Eur J Immunol lO(10): 737,198O. Hamilton TA, Wada HG, Sussman HH. Expression of human placental cell surface antigens on peripheral blood lymphocytes and lymphoblastoid cell lines. Stand J Immu- nol ll(2): 195,198O

Baclay AN, Letarte-Muirhead M, Williams AF, Faulkes RA. Chemical characterisation of the Thy-l glycoproteins from the membranes of rat thymocytes and brain. Nature 263: 563,1976.

Cotner T, Mashimo H, Kung PC, Goldstein G, Stmminger JL. Human T cell surface antigens bearing a structural relationship to HLA antigens. Proc Nat1 Acad Sci USA 78(6): 3858.1981. Bevan MJ, Hunig T. T cells respond preferentially to antigens that are similar to self H-2. Pmc Natl Acad Sci USA 78(3): 1843, 1981. Shaw S, Shearer GM, Biddison WE. Human cytotoxic T-cell responses to type A and type B influenza virus can be restricted by different HLA antigens, Implications for HLA polymorphism and genetic regulation. J Exp Med 151(l): 235,198O.

Tursz T, Fridman WH, Senik A et al. Human virus-infected target cells lacking HLA antigens resist specificT-lymphocyte cytolysis. Nature 269: 806, 1977.

Sethi KK, Stroehmann I, Brandis H. Human T-cell cultures from virus-sensitized donors can mediate virus-specific HLA-restricted cell lysis. Nature 286: 718,198O.

Pierce CW, Kapp JA. Functions of macrophages in antibody responses in vitro. Fed Proc 37(l): 86.1978.

Hansen GS, Rubin B, Sorensen SF, Svejgaard A. Impoxt-

35.

36.

37.

38.

39.

40.

41.

42.

43

44

83

ante of HLA-D antigens for the cooperation between human monocytes and T lymphocytes. Eur J Immunol 8: 520,1976.

45. Kumick JT, Altevogt P, Lindblom J et al. Long-term main- tenance of HLA-D restricted T cells specific for soluble antigens. Stand J Immunol 1 l(2): 131.1980.

46. Bodmer WF, Jones EA, Barnstable C, BodmerJG. Genetics of HLA: T major human histocompatibility system. Pmc RSoc Land (Biol) 201: 93,1978.

47. Daunter B. RISH III. Haplotype sharing in the immune

49.

50.

51.

52.

cytes to unfixed and fixed high endothelial cells of lymph nodes. J Immunol 123(5): 2369,197Q.

Berg EL, Goldstein LA, Jutila MA et al. Homing receptors and vascular addressins: Cell adhesion molecules that direct

lymphocyte traffic. Immunol Rev 108: 5,1989. Hamann A, Thiele HG. Molecules and regulation in lymphocyte migration. Immunol Rev 108: 18,198Q.

Pals ST, Horst E, Scheper RJ, Meifer CJLM. Mechanisms of human lymphocyte migration and their role in the pa- thogenesis of disease. Immunol Rev 108: 111,198Q.

Pabst R, Binns RM. Heterogeneity of lymphocyte homing physiology: several mechanisms operate in the control of

response. MedHypoth 1?-79,-i985.

migration to lymphoid and non-lymphoid organs in vivo. hnmunol Rev 108: 82,1989.

_

Viklicky V, Peknocova J, Polackova M. The significance

48. WoodmtTJJ. Rasmussen R4. In vitro adherence of lvmnho-

of the cell surface for the homing affiity of injected lymphoid cells in mice. Folia Biol (Pmha) 22(3): 159,1976. Heslop BF, Hardy BE. The distribution of 5’Cr-labelled syngeneic and allogeneic lymph node cells in the rat. Transplantation 11: 128,1971.

Degas L, Pla M, Colombani M. H-2 restriction for lymphocytes for homing into lymph nodes. Eur J hnmunol Q(10): 808.1979.

Binns RM, Pabst R, Licence ST. Classification of lymphocytes recirculating in the spleen. Immunology 44(2): 273, 1981.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

Herberman RB. Studies on the specificity of human cytotoxic antibody reactive with cultums of lymphoid cells. J Natl Cancer Inst 42(l): 69,1969.

Johannsen R. Sodlacek H. Specificity cytotoxic antibodies to autologous human lymphocytes treated with neuraminidase from Vibrio cholerae. Behring Inst MH 55: 209.1974.

Park MS, Terasaki PE, Byms G, Ayoub G. Cold-reactive antibodies to B lymphocytes and their absorption by platelets and red cells. Transplant Pmc Q(4): 1701. 1977. Daunter B. RISH VIII. Basic arguments. Med Hypoth previous article. Poppema S, Bhan AK, Reinherz EL, McCluskey RT, Schlossman SF. Distribution of T cell subsets in human lymph nodes. J Bxp Med 153(l): 30.1981. Pfnemnaier K, Trostmann H, Rollinghoff M, Wagner H. Temporary presence of self-reactive cytotoxic T lymphocytes during murinc lymphocytic choriomeningitis. Nature 258: 238,197s. Osband M, Parkmann R. The control of automactivity. I. Lack of autoreactivity in murine spleens is due to concomi- tantpresence of suppressor and autocytotoxic lymphocytes. J hnmunol 121(l): 179.1978.

Gozes Y, Umiel T, Meshorer A, Trainin N. Syngeneic GvH induced in poplitcal lymph nodes by spleen cells of old C57BU6mice. J hnmunol121(6): 2199.1978.

L’age-Stehr J, Diamantstein T. Induction of autoreactive T lymphocytes and their suppressor cells by cyclophospha-

84 MEDICAL HYF’OTHBSBS

70. Trainin N, Pecht M, Han&e1 ??I’. Thymic hormones: Indu- cers and regulators of the T-cell system. Immunology Today 4(l): 16,1983.

71. Cohen IR, Wekedc H. Regulation of autosensitization. The ! immune activation and specific inhibition of self-recogniz- ing thymus derived lymphocytes. J Exp Med 137(2): 224, 1973.

72. Peck AB, Wigzell H, Janeway C Jr, Andemson LC. Envi- ronmental and genetic control of T cell activation in vitro: a study using isolated alloantigen-activated T cell clones. Immunol Rev 35: 146,1977.

73. Volelfanger IJ, Milthorp P, Behelak Y et al. Naturally occurring immunosuppressive agents. I. The presence in normal pig liver of a factor possessing immunosuppressive properties with respect to pig lymphoid cells in vitro. Transplantation20(2): 130,197s.

74. Daunter B, Khoo SK, Mackay EV. Lymphocyte response to plant mitogem. Gynecol Oncol g(2): 198,1979.

mide. Nature 271: 663.1978. 66. L’age-Stehr J, Diamantstein T. Studies on induction and

control of cell-mediated autoimmunity. I. Induction of ‘autoreactive’ T-lymphocytes in mice by cyclophosphamide. Eur J Immunol g(9): 620,1978.

67. Reimann J, Diamantstein T. ‘Self-reactive’ T cells. I. In vivo reaction of T cells to transferred polyclonally activated syngeneic and autologous lymphoblasts. Immunobiology 157(4-S): 437,198O.

68. Reimamt J, Diamantstein T. ‘Self-reactive’ T cells. II. Transferred syngeneic lymphoblasts include T stimulator cells in vivo to which syngeneic T cells ‘respond’ in a syngeneic MLC in vitro. Immunobiology 157(4-5): 450, 1980.

69. Reimann J, Diamantstein T. ‘Self-reactive’ T cells. III. In vitro restimulation of T cells ‘responding’ in vivo or in vitro to syngeneic lymphoid cells. Immunobiology 157(4-5): 463,198O.

Documents

Immune response: Tissue specific T-lymphocytes