scholarly journals STUDIES ON NORMAL AND IMMUNE LYMPHOCYTE TRANSFER REACTIONS IN GUINEA PIGS, WITH SPECIAL REFERENCE TO THE CELLULAR CONTRIBUTION OF THE HOST

1972 ◽  
Vol 136 (6) ◽  
pp. 1545-1563 ◽  
Author(s):  
Siraik Zakarian ◽  
R. E. Billingham
Keyword(s):  
Guinea Pigs ◽  
Significant Proportion ◽  
Intradermal Injection ◽  
Lymphoid Cells ◽  
Delayed Hypersensitivity ◽  
F1 Hybrids ◽  
Genetic Constitution ◽  
F1 Hybrid ◽  
Immune Lymphocyte ◽  
Lymphocyte Transfer

Using guinea pigs of strains 2 and 13 and their F1 hybrids as experimental subjects, various lines of evidence have been obtained that in this species, as in all others tested, the only significant cellular antigens with which donor lymphocytes engage when normal and immune lymphocyte reactions are incited are radiosensitive leukocytes. Constitutive cells of the skin are unimportant. (a) The intensities of these reactions in irradiated subjects are dependent upon the peripheral leukocyte concentration. When this falls below a certain threshold no reactions are incitable. (b) Highly leukopenic animals are capable of developing immune lymphocyte transfer (ILT) reactions if normal lymphoid cells of their own genetic constitution are mixed with the putative attacking donor cells, as "supplementing antigen," before inoculation. (c) Radiation-chimeric strain 13 animals having F1 hybrid leukocytes in their bloodstream give typical ILT reactions when challenged intradermally with strain 13 anti-2 node cells. Exposure of strain 2 animals to 600 R does not prevent their becoming actively immunized if, 24 hr later, they are injected intradermally with strain 13 lymphocytes. However, this sensitization, revealed by the host's capacity to give delayed hypersensitivity reactions, wanes as leukopenia progresses. On the basis of this and other findings it is argued that the flare-up stage of the NLT reaction in preirradiated hosts is mainly an expression of host sensitivity against the transferred alien cells. Two unexpected observations have been made in the course of this study: (a) F1 hybrid animals developed what appeared to be a strong delayed hypersensitivity after intradermal inoculation with parental strain lymphoid cells or antigenic extracts prepared from them. (b) If strain 13 guinea pigs which had been sensitized against strain 2 tissue antigens by intradermal injection of lymphocytes 7 days beforehand were inoculated intravenously with strain 2 antigenic extract a significant proportion of the animals developed severe delayed necrotizing reactions, recall flares, at some or all of the healed skin inoculation sites.

scholarly journals AN ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS

1970 ◽  
Vol 132 (1) ◽  
pp. 181-197 ◽  
Author(s):  
J. Wayne Streilein ◽  
R. E. Billingham
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Transfer Reactions ◽  
F1 Hybrids ◽  
F1 Hybrid ◽  
Graft Versus Host ◽  
Immune Lymphocyte ◽  
Donor Cells ◽  
Lymphocyte Transfer

The epidermolytic syndrome that can be obtained at will in F1 hybrid hamsters by the cutaneous inoculation of adequate doses of parental strain lymphoid cells has been investigated to determine whether the cutaneous lesions are due to an autoimmune process arising from the severe, initial GVH reactions in the skin. It was amply demonstrated that inoculation of donor cells into the skin was of crucial importance to the development of epidermolysis. Parental strain lymphoid cells in similar doses delivered by any other route into normal F1 hybrids failed absolutely to incite the acute syndrome. If "immune lymphocyte transfer" reactions incited by donor cells in the host's skin were surgically removed at timed intervals after inoculation, only complete excision within 24 hr prevented the appearance of epidermolysis in F1 hybrid hosts, indicating that inoculated donor cells must remain within the confines of the skin for approximately 24 hr in order to evoke the disease, persistence for longer periods of time being unnecessary for the subsequent course of the disease. However, reconstitution experiments involving the intramuscular inoculation of suspensions containing mixtures of donor cells and host lymphoid cells, in the presence or absence of epidermal cells, unequivocally indicated that no intimate exposure of lymphoid cells to putative skin-specific antigens was essential. Similarly, the elicitation of generalized epidermolysis in F1 hybrids irradiated with 300 r and then inoculated intravenously with donor cells casts further doubt on the pathogenic importance of the skin as a source of tissue-specific antigen. The results of subsequent experiments indicated that host leukocytes, rather than parenchymal cells of the dermis or the epidermis, were important contributors of the transplantation antigenic stimulus. Moreover, a series of experiments, using (CB x MHA)F1 hybrid hosts that had been lethally irradiated and reconstituted with bone marrow cells from ALS-treated MHA donors, indicated that from 6 to 10 wk after reconstitution—when direct and immune lymphocyte transfer reactions showed a virtual absence of native F1 leukocytes from the circulation—donor cells obtained from specifically sensitized MHA donors were completely ineffective in inducing epidermolysis, while equivalent lymphoid cell inocula derived from CB donors evoked the cutaneous disease irrespective of the time elapsed since reconstitution. To explain these findings it is postulated that in hamsters, the primary targets in graft-versus-host disease incited by the intracutaneous inoculation of donor cells are leukocytes originating in bone marrow or lymph node, or both.

scholarly journals DELAYED HYPERSENSITIVITY

1957 ◽  
Vol 105 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Jonathan W. Uhr ◽  
A. M. Pappenheimer ◽  
M. Yoneda
Keyword(s):  
Guinea Pigs ◽  
Diphtheria Toxin ◽  
Intradermal Injection ◽  
Delayed Hypersensitivity ◽  
Toxigenic Strain ◽  
Skin Reactions ◽  
Minute Amount ◽  
Initial Infection ◽  
Toxigenic Strains

Guinea pigs infected by intradermal injection of living toxigenic diphtheria bacilli and protected by horse antitoxic globulin, given either before or after infection, develop delayed hypersensitivity of the tuberculin type to diphtherial proteins. The highest degree of hypersensitivity is specifically directed against diphtheria toxin (or toxoid) itself, although smaller delayed skin reactions may be evoked in sensitized animals by other diphtherial proteins common to both toxigenic and non-toxigenic strains. Animals sensitized to diphtheria toxin by infection with a toxigenic strain in this way react positively to the Schick test and their serum usually contains no detectable antitoxin 2 to 3 weeks after the initial infection. Animals infected with living non-toxigenic diphtheria bacilli become sensitized to proteins common to both toxigenic and non-toxigenic strains but do not show sensitivity to toxin. The observations suggest that a minute amount of toxoid, or of toxin comparable to that which might be liberated during infection, might induce the hypersensitive state if injected in the form of a complex with excess antitoxin. This prediction is verified by the results reported in the following paper (23).

scholarly journals Brief Report: Graft-Versus-Host Reaction in F1 Hybrid Mice Injected with Pre-Immunized Parental Thymus Cells

Blood ◽  
1964 ◽  
Vol 24 (6) ◽  
pp. 770-774 ◽  
Author(s):  
LUCIANO FIORE-DONATI ◽  
LUIGI CHIECO-BIANCHI ◽  
GIUSEPPE DE BENEDICTIS ◽  
GIUSEPPE TRIDENTE
Keyword(s):  
Lymphoid Cells ◽  
The Other ◽  
F1 Hybrids ◽  
Graft Versus Host Reaction ◽  
Host Reaction ◽  
F1 Hybrid ◽  
Graft Versus Host ◽  
Immunologic Activity ◽  
Thymus Cells ◽  
Hybrid Mice

Abstract Dissociated thymus cells are capable of initiating graft-versus-host reaction in (C3Hf/Gs x DBA/2)F1 hybrids only when derived from parental donors previously sensitized against the antigens of the other parental strain. The lower immunologic activity of thymus cells as compared with other lymphoid cells is presumably due to quantitative rather than qualitative differences in immunologically competent cells.

scholarly journals ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS

1972 ◽  
Vol 135 (3) ◽  
pp. 567-578 ◽  
Author(s):  
J. Wayne Streilein
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Antigenic Determinants ◽  
F1 Hybrid ◽  
Host Disease ◽  
Syrian Hamsters ◽  
Graft Versus Host ◽  
Refractory State ◽  
Lymphocyte Transfer ◽  
Additional Support

The so-called refractory state, one sequela of acute graft-versus-host disease, has been studied in adult (CB x MHA)F1 hybrid Syrian hamsters inoculated with sublethal numbers of MHA-anti-CB lymphoid cells. Intracutaneous challenge of these animals with 200 million MHA-anti-CB lymphoid cells after the acute syndrome subsided failed to evoke epidermal necrolysis, whereas a similar challenge administered to normal F1 recipients invariably resulted in lethal epidermolysis. Moreover, the gradual attrition of lymphatic tissues in these hosts and their fading capacity to display adequately immune lymphocyte transfer reactions in the skin coincided with increasing evidence of host refractoriness, suggesting a causal interrelationship. It was possible to circumvent refractoriness by challenging these animals intracutaneously with MHA-anti-CB cells if: (a) the hosts had been lethally irradiated and reconstituted with F1 hematopoietic cells, or (b) the intracutaneous inocula contained admixed F1 lymphoid cells. This evidence provides additional support for the hypothesis that in GVH disease donor lymphocytes attack primarily host lymphoid cells bearing offending homologous antigens. The GVH process can continue so long as these lymphocyte-bound antigens persist within the host, and will abate only as the aggregate host lymphatic mass is effectively destroyed (hamsters) or its antigenic determinants are masked by isoantibodies (rats, mice, man?). At this point, insufficient target tissues remain for rechallenge to incite significant recrudescence of the disease.

scholarly journals STUDIES OF DELAYED HYPERSENSITIVITY IN VITRO

1957 ◽  
Vol 106 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Lowell A. Glasgow ◽  
Herbert R. Morgan
Keyword(s):  
Skin Reaction ◽  
Guinea Pigs ◽  
Viral Antigen ◽  
Intradermal Injection ◽  
Mumps Virus ◽  
Delayed Hypersensitivity ◽  
Virus Infections ◽  
Splenic Macrophages

Guinea pigs experimentally infected with mumps virus develop a delayed, hypersensitive skin reaction following the intradermal injection of heat-inactivated mumps virus. This in vivo hypersensitivity is accompanied by a state of cellular hypersensitivity which can be demonstrated in vitro by the addition of mumps viral antigen to cultures of splenic macrophages, following which they become less motile and undergo lysis. These observations support the hypothesis that the state of hypersensitivity which develops early in mumps virus infections may have a role in the pathogenesis of the disease.

scholarly journals AN ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS

1970 ◽  
Vol 132 (1) ◽  
pp. 163-180 ◽  
Author(s):  
J. Wayne Streilein ◽  
R. E. Billingham
Keyword(s):  
Parental Strain ◽  
Lymphoid Cells ◽  
Autoimmune Response ◽  
Antigenic Determinants ◽  
Genetic Constitution ◽  
F1 Hybrid ◽  
Graft Versus Host ◽  
Major Histocompatibility Locus ◽  
Histocompatibility Locus ◽  
Parenchymal Cells

F1 hybrid hamsters derived from genetically disparate strains develop a severe and often lethal cutaneous disorder when inoculated intracutaneously with immunologically competent lymphoid cells from either parental strain, The disease is characterized clinically by extensive epidermal necrolysis, and histologically by a complete dissolution of the dermal-epidermal junction. The requisites for elicitation of this syndrome were determined to be: (a) the parental strains must differ from each other at a major histocompatibility locus, and (b) the donor inoculum must contain immunologically competent parental strain cells. In addition it was found that specifically sensitized cells surpassed normal unsensitized ones in their ability to elicit the disease, and that the disease can be transferred adoptively from affected to normal F1 hosts by means of lymphoid cells. On the basis of these observations, it was concluded that the disease was immunologic in nature, and graft-versus-host in type. However, a series of critical studies failed to demonstrate that the epidermolysis had an immunogenetically specific basis, thus invalidating the provisional assumption that this lesion resulted from a direct immunologic attack upon parenchymal cells of the epidermis and dermis. With the aid of radiation chimeras, it was clearly established that typical epidermolysis could be induced in skin of the same genetic constitution as the attacking donor lymphoid cells. This paradox was taken into account by the possibility that, amid the intense local cutaneous graft-versus-host reactions, "skin-specific" antigenic determinants are bared which incite a quasi autoimmune response that in turn is responsible for the epidermolytic lesions.

scholarly journals CUTANEOUS HYPERSENSITIVITY REACTIONS TO CELLULAR ISOANTIGENS IN RATS

1967 ◽  
Vol 126 (3) ◽  
pp. 455-473 ◽  
Author(s):  
J. W. Streilein ◽  
R. E. Billingham
Keyword(s):  
Lymphoid Cells ◽  
Hypersensitivity Reactions ◽  
Adult Rats ◽  
Backcross Population ◽  
F1 Hybrid ◽  
Inflammatory Reactions ◽  
Cutaneous Hypersensitivity ◽  
Histocompatibility Locus ◽  
Lymphocyte Transfer ◽  
Delayed Cutaneous Hypersensitivity

Rats have been shown to be capable of displaying the various kinds of delayed cutaneous hypersensitivity reactions attributable to transplantation immunity previously described in guinea pigs, hamsters, rabbits, dogs, and man. The rat is unlike most other species in that much larger numbers of lymphoid cells are needed to incite these cutaneous reactions. With direct, transfer, or normal lymphocyte transfer reactions, the cutaneous responses were greater when donor and recipient differed at the Ag-B histocompatibility locus than when donor and recipient shared the same Ag-B alleles. An experiment was performed in which adult rats of a genetically defined backcross population, resulting from matings between DA and (DA x Lewis) F1 hybrid rats, were inoculated intradermally with lymph node cells from DA rats sensitized against tissues from Lewis-strain donors. Some of the R2 animals gave a biphasic transfer reaction with peak reactivities occurring first at 48 hr and recurring at 96–120 hr, while the others lacked this second component. Hemagglutination tests revealed that the R2 rats giving the biphasic response possessed the Ag-B,1 antigen, which is also present in Lewis rats, whereas rats which gave monophasic reactions were homozygous for the Ag-B,4 antigenic determinant which is present in the DA strain. This suggested that the recall flare at 96–120 hr reflects proliferative activity on the part of the inoculated cells confronted by the disparate Ag-B isoantigen in the host's dermis. Skin homografts from R1 animals bearing the Ag-B,1 antigen were uniformly rejected by DA hosts in 11 days or less, while grafts from backcross animals homozygous for the Ag-B,4 antigen usually lived longer, being rejected in 9 to 27 days. Evidence is also presented which suggests that specific isoantibodies may act synergistically with immune lymphocytes to bring about cutaneous inflammatory reactions in the rat.

scholarly journals DELAYED HYPERSENSITIVITY

1957 ◽  
Vol 105 (1) ◽  
pp. 11-24 ◽  
Author(s):  
Jonathan W. Uhr ◽  
S. B. Salvin ◽  
A. M. Pappenheimer
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Intradermal Injection ◽  
Delayed Hypersensitivity ◽  
Protein Antigens ◽  
Single Protein ◽  
Maximal Sensitivity ◽  
Degree Of Sensitization ◽  
Circulating Antibody ◽  
General Method

A general method for induction of the delayed hypersensitive state directed against single protein antigens is described. The method consists of intradermal injection of minute amounts of washed immune precipitates containing the antigen in question. Provided the specific precipitates are formed in the region of antibody excess, maximal sensitivity develops at least 2 to 3 weeks before detectable circulating antibody is formed in guinea pigs against the sensitizing antigen. Neither adjuvant nor killed acid-fast bacteria are required for induction of the delayed hypersensitive state although the degree of sensitization is considerably increased when the sensitizing material is incorporated in Freund's complete adjuvant. Characteristics of the "delayed" as opposed to the "immediate" hypersensitive states in the guinea pig are described and implications of the findings are discussed.

scholarly journals SPECIFICITY OF PASSIVELY TRANSFERRED DELAYED HYPERSENSITIVITY

1963 ◽  
Vol 118 (3) ◽  
pp. 341-352 ◽  
Author(s):  
John S. Najarian ◽  
Joseph D. Feldman
Keyword(s):  
Skin Lesion ◽  
Guinea Pigs ◽  
Specific Antigen ◽  
Test Site ◽  
Total Radioactivity ◽  
Lymphoid Cells ◽  
Delayed Hypersensitivity ◽  
Specific Test ◽  
Autoradiographic Analysis ◽  
Reciprocal Arrangement

Guinea pigs were injected intravenously with lymphoid cells sensitized to tubercle bacilli (TBC cells) and with lymphoid cells sensitized by contact to a simple chemical, dinitrofluorobenzene (DNFB cells). In each transfer, either the TBC cells or the DNFB cells were labeled with H3-thymidine. Immediately after transfusion, each recipient was skin tested with PPD and DNFB. 24 hours later these lesions were removed for determination of total radioactivity and for autoradiographic analysis. When TBC cells labeled with H3-thymidine were transferred with DNFB cells without an isotopic marker, the total radioactivity and the concentration per gram of skin lesion were greater in the PPD test sites. In the reciprocal arrangement, when DNFB cells labeled with H3-thymidine were transfused with TBC cells without an isotopic tag, the total radioactivity and the concentration per gram of skin lesion were greater in the DNFB test site. Similar results were obtained in guinea pigs which were actively immunized by tubercle bacilli and passively by transfer of DNFB cells. Autoradiographic analysis of test sites from guinea pigs passively transferred with both types of sensitized cells confirmed these findings. By calculation, only a very small number of transferred sensitized cells reached the specific test lesion. Most of the cellular infiltrate was derived from the responding host. The specificity of the reaction of delayed hypersensitivity was apparently achieved by retention of the sensitized cells after they had arrived by chance at the specific antigen depot and was not due to a non-specific stickiness of sensitized or inflamed lymphoid cells.

scholarly journals FUNCTION OF MACROPHAGES IN ANTIGEN RECOGNITION BY GUINEA PIG T LYMPHOCYTES

1973 ◽  
Vol 138 (5) ◽  
pp. 1194-1212 ◽  
Author(s):  
Alan S. Rosenthal ◽  
Ethan M. Shevach
Keyword(s):  
Dna Synthesis ◽  
Guinea Pigs ◽  
Lymphocyte Proliferation ◽  
Lymphoid Cells ◽  
Histocompatibility Complex ◽  
Immune Lymphocyte ◽  
Functional Interference ◽  
Lymphocyte Dna Synthesis ◽  
Kinetics Of

Antigen activation of DNA synthesis in immune thymus-derived lymphocytes of guinea pigs requires the cooperation of macrophages and lymphocytes. We have investigated the role of histocompatibility determinants in this macrophage-lymphocyte interaction using cells from inbred strain 2 and 13 guinea pigs. The data demonstrate that efficient presentation of macrophage-associated antigen to the lymphocyte requires identity between macrophage and lymphocyte at some portion of the major histocompatibility complex. The failure of allogeneic macrophages to effectively initiate immune lymphocyte proliferation was not the result of the presence of an inhibitor of blastogenesis released in mixtures of allogeneic cells, peculiarities of the antigen or lymphoid cells employed, nor differing kinetics of activation by allogeneic macrophages. In addition, data were presented that demonstrated that alloantisera inhibit lymphocyte DNA synthesis by functional interference with macrophage-lymphocyte interaction.

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