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PubMed1969

Cellular differentiation of the immune system of mice. IV. Lack of class differentiation in thymic antigen-reactive cells.

Thymocytes and marrow cells of unprimed donor mice were mixed in vitro and transplanted into X-irradiated syngeneic mice. 18 hr later, sheep erythrocytes were injected to induce immune responses. Splenic plaque-forming cells (PFC) secreting IgM (direct PFC) or IgG (indirect PFC) hemolytic antibody were enumerated at the time of peak responses. By transplanting graded and limiting numbers of thymocytes with 4 x 10(7) marrow cells, inocula were found which contained one or a few thymic antigen-reactive cells (ARC) reaching the recipient spleens, interacting with marrow cells, and inducing PFC formation. The frequency values of ARC inferred from direct and indirect plaque assays were very similar, 1 in approximately 10(7) thymocytes. Furthermore, statistical analysis indicated that the formation of direct PFC was not independent of the formation of indirect PFC. This was interpreted to mean that ARC were not specialized themselves and did not determine the molecular class of antibody to be secreted after interaction with marrow cells. Spleens of thymus-marrow grafted mice containing one or two ARC and non-limiting numbers of marrow precursors of PFC (P-PFC), had direct and indirect PFC clustered in several focal areas. Assuming that each focal area represented the progeny of one P-PFC that had interacted with ARC, these results confirmed the statistical evidence for lack of class differentiation in thymic ARC, and also indicated that each ARC or its progeny cells interacted with more than one P-PFC of either class.

Animals↗
PubMed1969

Cellular differentiation of the immune system of mice. V. Class differentiation in marrow precursors of plaque-forming cells.

Marrow cells and thymocytes of unprimed donor mice were mixed in vitro and transplanted into X-irradiated syngeneic hosts. 18 hr later sheep erythrocytes were injected to induce immune responses. Splenic plaque-forming cells (PFC) secreting IgM (direct PFC) or IgG (indirect PFC) hemolytic antibody were enumerated at the time of peak responses. By transplanting graded and limiting numbers of marrow cells with 5 x 10(7) thymocytes, inocula were found that contained few precursors of PFC (P-PFC) reaching the recipient spleens, interacting with thymocytes, and generating PFC. However, the frequency of responses in relation to the number of grafted marrow cells did not follow Poisson statistics, presumably because the interaction of marrow cells with thymocytes was more complex than a single or a one-to-one cell event. The frequency of direct PFC responses was greater than that of indirect PFC responses in 13 of 15 groups of mice tested. This was interpreted as evidence for the existence of two classes of P-PFC, each of which was restricted to generate either direct or indirect PFC. The precursors of direct PFC were approximately 15 times more frequent than those of indirect PFC. Since thymic antigen-reactive cells were not differentiated for antibody class, it follows that antigen-sensitive units reactive to sheep erythrocytes owe their class restriction to specialized marrow cells. Specialization of P-PFC may have arisen within marrow cell lines by differentiation, or may have been conferred upon P-PFC by interaction with other cells, including those of the irradiated host.

Animals↗
PubMed1969

Cells involved in the immune response. XII. The differing responses of normal rabbit lymphoid cells to phytohemagglutinin, goat anti-rabbit immunoglobulin antiserum and allogeneic and xenogeneic lymphocytes.

Cells of the different lymphoid organs in the normal adult rabbit were investigated for their capacity to respond in vitro to a number of stimuli, such as phytohemagglutinin (PHA), anti-rabbit immunoglobulin antiserum (GARIG) and allogeneic and xenogeneic lymphoid cells, and for their capacity to adsorb radioactively-labeled anti-immunoglobulin antiserum. The bone marrow cells responded minimally to PHA, GARIG, and the allogeneic and xenogeneic stimuli. The thymus cells were unable to respond to stimulation with GARIG although they responded to the other stimuli. The cells of the other lymphoid organs tested responded to all the mitogenic agents, to varying degrees. On the basis of the results presented and the findings of other investigators, it is concluded that: 1. The response of the cells to GARIG indicates a potential capacity to mediate humoral immunity and requires the presence of immunoglobulin or immunoglobulin-like recognition sites on the cell surface. 2. The response of the cells to PHA and allogeneic and xenogeneic cells indicates a potential capacity to mediate cellular immunity and does not necessitate the presence of immunoglobulin-recognition sites on the cell surface. 3. The thymus in the normal adult rabbit consists of cells capable of mediating cellular immunity only. 4. The other lymphoid organs appear to possess cells capable of mediating humoral and cellular immunity.

Animals↗
PubMed1970

Contact sensitivity in the mouse. IV. The role of lymphocytes and macrophages in passive transfer and the mechanism of their interaction.

Contact sensitivity skin reactions were produced in mice by immunization with 2-phenyl-4-ethoxymethylene oxazolone (oxazolone) and detected by the increase in ear thickness after challenging the ears with 2% oxazolone. These skin reactions can be transferred from immunized donors to irradiated recipients by peritoneal exudate cells induced by thioglycollate. The peritoneal exudate cells were separated into purified macrophage and purified lymphocyte populations. Both cell populations transferred skin reactions. However, their time course was different. The reactions produced by lymphocytes were greater at 24 hr than at 12 hr while the reactions produced by macrophages declined slightly between 12 and 24 hr. The working hypothesis was formed that the peritoneal lymphocytes conveyed a factor (presumptive cytophilic antibody) to peritoneal macrophages which enabled them to transfer ear reactions. Experiment showed that peritoneal and lymph node lymphocytes from sensitized donors within a Millipore chamber conveyed a factor to macrophages outside the chamber which enabled them to transfer ear reactions. In contrast, peritoneal macrophages (from sensitized donors) within the chamber and peritoneal lymphocytes outside the chamber were inactive. These findings suggested that there are three modes of immunological tissue damage: hypersensitivity mediated by lymphocytes (classical delayed hypersensitivity), hypersensitivity mediated by circulating antibody (classical immediate type hypersensitivity), and hypersensitivity mediated by macrophages which have passively acquired a factor (macrophage-mediated hypersensitivity).

Animals↗
PubMed1970

Transfer of antibody production with cells from bursa of Fabricius.

F(1) hybrid chicks isogenic for the strong B histocompatibility locus and for most weak H-loci were X-irradiated on day 1 after hatching, injected intraperitoneally on day 2 with dispersed cells of bursa, spleen, or thymus from 4- or 10-wk-old F(1) hybrid donors, and immediately challenged by the same route with either Brucella abortus, sheep erythrocytes, or a mixture of both together. The agglutinin titers were measured in sera obtained 1 wk later. With 4-wk-old donors, a greater primary response to Brucella abortus was obtained after transfers of cells from bursa than from spleen, while thymus was much less effective. With 10-wk-old donors, the decreasing order of response was spleen, bursa, thymus. Only splenic cells were effective in transferring a response to sheep erythrocytes, at either donor age. In tests of synergism by cell mixtures from pairs of organs, the only positive finding was a modest augmentation of titer against sheep erythrocytes by bursa + spleen as compared with spleen alone. Bursal cells from 6- or 10-wk-old donors were effective in transferring a response to sheep erythrocytes when antigen injection was delayed until 5 days after cell transfer. Splenic cells from hormonally bursectomized donors were ineffective in transferring a primary response, even when the donors had been injected with antigen 1 wk before transfer. Preimmunization of normal donors led to marked increases in the responses to Brucella abortus produced by transferred splenic or thymic cells. With bursal cells, an increased response was obtained only if the interval between preimmunization and transfer was 17 rather than 7 days. With the 17-day interval, both bursal and thymic cells could also transfer a response to sheep erythrocytes. The primary sera to Brucella abortus produced after transfers of bursal or splenic cells contained almost entirely 19S antibodies. A 7S component was found in all the secondary sera tested.

Animals↗
PubMed1970

Carrier function in anti-hapten immune responses. II. Specific properties of carrier cells capable of enhancing anti-hapten antibody responses.

Transfer of live lymphoid cells from BGG-immunized strain 2 guinea pigs into syngeneic animals primed with DNP-OVA prepares the recipients for a markedly enhanced secondary anti-DNP antibody response upon challenge with DNP-BGG. This phenomenon has been demonstrated when the recipients were challenged 1 day after cell transfer, but it was considerably more striking when an interval of 6 days was allowed between transfer of cells and challenge with antigen. As demonstrated in the preceding paper (6), BGG preimmunization enhanced anti-DNP antibody responses to challenge with DNP-BGG. An analysis of the characteristics of substances to which preimmunization was effective in enhancing subsequent anti-hapten responses was made. It was shown that preimmunization of strain 13 guinea pigs with a copolymer of glutamic acid and lysine (GL), to which these animals are genetically unable to accord an immune response, failed to prepare them for an enhanced anti-DNP response to DNP-GL. Tolerance to BGG specifically abrogated the capacity of subsequent BGG immunization to prepare DNP-OVA primed rabbits for an enhanced anti-DNP response to DNP-BGG. Sensitization of animals to haptens by preimmunization with hapten-protein conjugates failed to prepare them for enhanced primary or secondary antibody responses to other determinants associated with that hapten on a different carrier. These studies indicate that the enhancing effect of carrier preimmunization reflects a cooperative interaction between lymphoid cells specific for carrier and cells specialized for haptenic determinants. Furthermore, the capacity of a substance to behave as a carrier requires more than its possession of a variety of antigenic determinants.

Animals↗
PubMed1970

Synergism of thymus and bone marrow in the production of gra a5hilgard HR: Synergism of thymus and bone marrow in the production of graft-versus-host splenomegaly in x-irradiated hosts.

Graft-versus-host splenomegaly may be elicited from 500 R X-irradiated F(1) hybrid hosts if the hosts are injected with bone marrow cells and thymus cells from parental strain donors. Cells from thymus only or bone marrow only will not elicit graft-versus-host splenomegaly in these hosts. In this requirement for cells from both sources, the bone marrow cells play a nonimmunologic, proliferative role in the splenomegaly, and the thymus cells carry out the immunologic attack. Thus the mechanism of this synergism is quite different from that reported for the humoral immune response to sheep erythrocytes in which both thymus and marrow interact in the production of the specific immunologic response itself.

Animals↗
PubMed1970

Cellular basis of the genetic control of immune responses to synthetic polypeptides. I. Differences in frequency of splenic precursor cells specific for a synthetic polypeptide derived from multichain polyproline ((T,G)-Pro--L) in high and low responder inbred mouse strains.

SJL mice are high responders to the synthetic multichain polypeptide antigen (T,G)-Pro--L, whereas DBA/1 mice are low responders (10, 11). In order to determine whether the genetic control of immune response can be correlated with the number of antigen-sensitive precursor cells, spleen cell suspensions from normal and immunized SJL and DBA/1 donor mice were transplanted into lethally X-irradiated syngeneic recipients (incapable of immune response) along with (T, G)-Pro--L. Anti-(T, G)-Pro--L responses (donor-derived) were assayed in the sera of the hosts 12-16 days later. By transplanting graded and limiting numbers of spleen cells, inocula were found which contained one or a few antigen-sensitive precursors reactive with the immunogen. Using this method to estimate the relative numbers of such cells for the high responder SJL strain, one precursor was detected in approximately 1.3 x 10(6) and approximately 7.2 x 10(6) spleen cells from immunized and normal donors, respectively. In contrast, one precursor was detected in about 30 x 10(6) spleen cells from low responder DBA/1 mice, irrespective of whether the donors had been immunized. These results indicate that the genetic control of immunity to the synthetic polypeptide antigen investigated is directly correlated to the relative number of precursor cells reactive with the immunogen in high and low responder strains.

Animals↗
PubMed1972

The immunologically specific retention of recirculating long-lived lymphocytes in lymph nodes stimulated by xenogeneic erythrocytes.

The lymph nodes of mice actively or adoptively immunized to sheep RBC and/or chicken RBC selectively retain long-lived lymphocytes after challenge with the appropriate antigen. This retention is demonstrable within 8 hr of the time of stimulation, though it probably begins even before this, and it is essentially complete within the first 24 hr. A similar selective retention is seen in nodes regional to the injection of some nonimmunogenic substances such as turpentine, but not others such as colloidal carbon or syngeneic RBC. In animals adoptively immunized to sheep and chicken RBC simultaneously, there is a preferential accumulation of the labeled long-lived lymphocytes of donors immunized to sheep RBC in lymph nodes challenged with sheep RBC, and a preferential accumulation of lymphocytes (labeled with a different radioisotope) from donors immunized to chicken RBC in lymph nodes challenged with this antigen. This immunologically specific component is demonstrable whether the antigen is given before or after adoptive immunization, suggesting that the only labeled cells capable of specific localization in this system are those cells that normally remain in the recirculating pool. In the present experiments, 31 out of 31 sets of antigenically stimulated lymph nodes have shown radiochemical evidence of immunological specificity in the distribution of donor lymphocytes between them, while corresponding sets of nonstimulated lymph nodes have shown only small random variations in the distribution of donor cells. Two different mechanisms are postulated whereby antigenic stimulation can alter the traffic of recirculating long-lived lymphocytes through stimulated lymph nodes. One affects recirculating cells of a particular immunological specificity, while the other affects recirculating cells without regard to their immunological specificity.

Animals↗
PubMed1973

The allogeneic effect in inbred mice. 3. Unique antigenic structural requirements in the expression of the phenomenon on unprimed cell populations in vivo.

The allogeneic effect has been shown to replace the requirement for carrier-specific helper thymus-derived (T) lymphocytes in secondary antihapten antibody responses in guinea pigs or mice. Attempts to enhance primary antibody responses to either 2,4-dinitrophenyl (DNP)-keyhole limpet hemocyanin (KLH) or DNP-ovalbumin (OVA) by the allogeneic effect have failed, and frequently result in suppression. However, the present studies have demonstrated a clear allogeneic effect on primary anti-DNP responses to a DNP-conjugate of the copolymer of D-glutamic acid and D-lysine, DNP-D-GL. This compound, for which no carrier-specific helper T cells exist, normally induces a state of DNP-specific tolerance in the doses employed. However, normal (BALB/c x A/J)F(1) recipients developed primary anti-DNP antibody responses, and of the IgG class, when DNP-D-GL was administered shortly after the transfer of allogeneic parental A strain lymphoid cells. To test the possibility that the presence of KLH-specific T lymphocytes might inhibit the expression of the allogeneic effect on the primary response to DNP-KLH, studies were undertaken using T cell-depleted spleen cells. In this model, the allogeneic effect again enhanced the primary response to DNP-D-GL, but still failed to enhance the primary response to DNP-KLH. These studies indicate that the structure of the molecule employed and its specific interaction with the bone marrow-derived (B) cell membrane may be critical in the capacity of primed and unprimed B cells to be influenced by the allogeneic effect.

Animals↗
PubMed1975

Early cellular events in a systemic graft-vs.-host reaction. I. The migration of responding and nonresponding donor lymphocytes.

A systemic graft-vs.-host (GVH) reaction was initiated by the intravenous injection of parental strain thoracic duct lymphocytes (TDL) into irradiated F1 hybrid recipients with in-dwelling thoracic duct cannulae. The migration of the donor lymphocytes was followed by labeling them in vitro with either [3H] or [14C]uridine and measuring radioactivity by scintillation counting of the spleen and lymph nodes of the recipients removed 24 h after injection and in TDL collected throughout this period. The localization of labeled cells was always compared to that of a reference population of nonreactive lymphocytes, e.g. F1 hybrid, labeled with the alternative isotope (Fig. 1). A consistent surplus of the reactive label was found in the spleen which was balanced by a deficit of the reactive label in TDL; lymph nodes gave intermediate values. The same distribution pattern was noted when the reference population was a specifically unresponsive population of the parental strain. This differential distribution depends on recognition of the recipient's Ag-B antigens because when normal lymphocytes were injected together with specifically unresponsive lymphocytes into a "third party" F1 hybrid (against which both populations were reactive) there was no surplus of the normal cells in the spleen and no deficit in the lymph. Moreover in an Ag-B identical strain combination there was no detectable difference in the distribution of reactive and nonreactive populations. The distribution of a labeled reaction population can be accounted for if a substantial minority of cells are immobilized in the spleen and lymph nodes as a consequence of antigen recognition (Fig. 3). When the donor cells in the spleen were assayed 24 h after injection there was paradoxically a slight reduction in their specific GVH activity, which is at least partly because they are under-represented in a single cell suspension. The size of the splenic surplus (23%) and the thoracic duct deficit (12%) suggested that the minority of nonimmune lymphocytes which recognize each Ag-B complex carry 12% of the radioactive label in the original population. It is argued that this provides a near estimate of the frequency of T lymphocytes which can recognize each Ag-B antigenic complex.

Animals↗
PubMed1978

Migratory behavior of lymphocytes with specific reactivity to alloantigens. II. Selective recruitment to lymphoid cell allografts and their draining lymph nodes.

A dual-antigen, dual-isotope assay has been used to monitor the migratory behavior of selectively labeled antiallogeneic lymphocytes in mice challenged subcutaneously in all four foot pads with semiallogeneic spleen cells. 3H-labeled anti-C3H and 14C-labeled anti-C57BL lymphocytes of DBA/2J origin were pooled and adoptively transferred to multiple groups of previously challenged DBA/2J recipients. In some of the studies, separate groups of recipients were challenged with either CDF or BDF spleen cells in all four paws, whereas in others CDF spleen cells were used to challenge the right paws of each mouse in the group and BDF spleen cells to challenge the left paws of each mouse in the group. At intervals varying from 24 to 96 h after challenge, a subgroup of four mice from each appropriate group was sacrificed and the relative numbers of anti-C3H and anti-C57BL lymphocytes present in the challenged paws, draining lymph nodes, and other tissues of each mouse were inferred from the mean 3H/14C ratios of the respective tissues of that subgroup. The results of these studies firmly establish that specific antiallogeneic lymphocytes are selectively recruited to the paws and draining lymph nodes of mice challenged subcutaneously in the foot pads with semiallogeneic spleen cells and are deleted from their circulating blood and nondraining lymph nodes. A mechanism for antigen-induced selective recruitment and its possible functional significance in tumor immunology are discussed.

Animals↗
PubMed1981

Induction of lymphoid cell chimerism in noninbred, histocompatible rabbits. A new model for studying allotype suppression in the rabbit.

Noninbred rabbits, matched with regard to the major histocompatibility complex (RLA-A and RLA-D loci) but mismatched for Ig allotypes, served as donors (adult) and recipients (newborn) of lymphoid cells. Lasting chimerism regularly followed the transfer of 1 x 10(8)-3 x 10(8) spleen, lymph node, or bone marrow cells, as indicated by the continued production of Ig with allotypic determinants of both donor and recipient. Typically, Ig of donor allotype accounted for 25-50% of total allotypic Ig at 4 wk of age and the amount of donor Ig produced remained stable for up to 20 mo. Total allotypic Ig levels remained normal in the chimeric rabbits. "Chimeric drift" or a gradual diminution of donor products over a period of several months, occurred in some individuals. Transfer of lymphoid cells from allotype-suppressed adult donors to newborns of appropriate allotypes did not result in specific suppression of the target allotype in the recipients. Other experiments showed that lymphoid cells from suppressed donors adoptively transferred to histocompatible recipients continued to synthesize Ig of the nonsuppressed type only. The suitability of using an outbred population of histocompatible but allotype-mismatched rabbits for analyzing allotype suppression and other immunoregulatory phenomena is demonstrated by the results presented here.

Animals↗
PubMed1982

Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis.

Autoimmune oophoritis that develops in A/J mice after neonatally thymectomy (NTx) was prevented by a single intraperitoneal injection of spleen cells or thymocytes from normal adult female mice. Prevention of oophoritis was achieved when spleen cells were given within 2 wk after Tx. When spleen cells were obtained from neonatally oophorectomized mice, four times more cells were required for the prevention of oophoritis, but those from the mice oophorectomized on day 7 after birth had equivalent capacity to prevent oophoritis to those from normal female mice. The spleen cells from normal A/J mice that prevented the development of oophoritis in NTx A/J mice were Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, sensitive to in vitro irradiation with 400 rad, resistant to administration of cyclophosphamide or anti-thymocyte serum, and were not eliminated by adult thymectomy. Thymocytes with oophoritis-preventing capacity were also found to be Lyt-1+,23- and TL-1,2,3-. These results seem to correlate well with the finding that the Lyt-1 subpopulation is substantially decreased in NTx mice. The results suggest that, in this post-thymectomy autoimmune oophoritis, NTx abrogates the Lyt-1 T cell subpopulation that serves as suppressive or regulatory cells over developing self-reactive cells directed toward ovarian antigens, and eventually may cause autoimmune oophoritis.

Aging↗
PubMed1984

Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2.

In previous in vitro studies, we have shown that murine splenocytes or cancer patient lymphocytes incubated in IL-2 become lytic for fresh syngeneic or autologous tumors. We have now performed the adoptive transfer of such lymphokine-activated killer (LAK) cells in a murine B16 metastasis model to test their in vivo efficacy. 1 X 10(8) LAK cells, infused intravenously into C57BL/6 mice with established B16 pulmonary metastases, led to a marked decreased in the number of lung nodules and improved survival. LAK cells administered 3 d after amputation of a tumor-bearing limb also decreased the incidence of spontaneous pulmonary metastases. LAK cells generated from tumor-bearer splenocytes had effects equivalent to those from normal animals, and this antimetastatic effect of the LAK cells did not require the prior administration of cyclophosphamide or other immunosuppressants. Fresh or unstimulated splenocytes had no effect. The antitumor effectors and precursors in vivo and in vitro were Thy-1+. The lymphokine required for the activation appeared to be interleukin 2 (IL-2), since incubation in partially purified supernatants from PMA pulsed EL-4 or Con A-pulsed splenocytes or purified Jurkat IL-2 led to the generation of LAK cells equally active in vivo. The use of IL-2-activated cells may provide a valuable method for the adoptive therapy of human neoplasms as well.

Animals↗
PubMed1985

Synergy between adjuvant arthritis and collagen-induced arthritis in rats.

Adjuvant arthritis (AA) in rats is susceptible to cell-mediated passive transfer. Collagen-induced arthritis (CIA) in rats is susceptible to passive transfer with antibody to type II collagen. We report here the development of strikingly severe arthritis in Lewis rats as the result of synergy between passively transferred antibody to type II collagen from rats with CIA and concanavalin A (Con A)-stimulated lymph node or spleen cells from syngeneic rats with AA. Similar synergy was seen in rats with AA given anticollagen antibody, in rats with CIA given Con A-stimulated adjuvant spleen cells, and in rats actively immunized with CII and complete Freund's adjuvant. The synergistic process caused a very severe polyarthritis, characterized by marked swelling and erythema in all the joints of the distal extremities, with histologic and radiographic evidence of early, extensive erosion of articular cartilage. Synergy was apparent if the lymphoid cells from AA rats were given up to 1 mo after a single injection of anticollagen antibody. No synergy was seen when normal rat immunoglobulin or anti-ovalbumin antibody was substituted for anticollagen antibody, when Con A-stimulated lymphoid cells from normal rats or donors with CIA were used, or when Con A-stimulated AA lymphoid cells were irradiated before transfer. Synergy between separate immune effector mechanisms may represent a general phenomenon in the pathogenesis of inflammatory joint disease.

Animals↗
PubMed1985

Synergism between T and non-T cells in the in vivo induction and in vitro expression of graft-vs.-host disease-induced natural suppressor cells.

We have been studying the mitogen hyporesponsiveness and immunosuppression induced in chronic murine graft-vs.-host disease (GVHD) induced across minor histocompatibility (MiHA) barriers. In this system, donor and recipient mice are major histocompatibility complex- and mls-identical, and are nonreactive in primary mixed leukocyte reactions. Spleen cells from B10.D2 (H-2d, mls b) mice were injected into irradiated (600 rad) BALB/c (H-2d, mls b) recipients. Recipient spleen cells are hyporesponsive to mitogens, and contain natural suppressor (NS) cells. We investigated the cellular requirements for both the in vivo induction and the in vitro expression of this GVH suppression. T cells are required in the graft, but they are not sufficient to induce suppression, and a non-T cell population is also required for maximum induction in vivo. T cells are also required for the maximum expression of NS cell suppressive ability in vitro. Early in the course of GVH, the suppressor cells are able to suppress the Con A and LPS response of all mouse strains tested (except for the relative difficulty in suppressing the B10.D2 LPS response). Later, they become almost completely unable to suppress the B10.D2 LPS response; while still being able to suppress the Con A and LPS response of all other strains tested (including the B10.D2 Con A response). This inability to suppress a B10.D2 LPS response can be brought back to almost complete suppression by the addition of concanavalin A supernatant (CAS). We present a hypothesis to explain what may be a common mechanism for GVH-induced suppression, total lymphoid irradiation-induced suppression, and neonatal tolerance. These situations all include rapidly proliferating lymphohematopoietic stem cell populations, and also have large numbers of NS cells. NS cells can suppress proliferating lymphoid populations, and their development and activity are greatly enhanced by T cell signals such as are supplied by donor T cells in chronic GVHD. Thus, NS cells may feed back on and downregulate self-reactive T cells or T cells responding to introduced foreign antigens.

Animals↗
PubMed1989

Identification of an immunodominant and highly immunopathogenic determinant in the retinal interphotoreceptor retinoid-binding protein (IRBP).

Interphotoreceptor retinoid-binding protein (IRBP), a glycoprotein specific for the retina and pineal gland, induces inflammatory changes in these two organs in immunized animals. We report here on the identification of an immunodominant determinant of bovine IRBP that is highly immunogenic and immunopathogenic in the Lewis rat. The peptide, which comprises the sequence 1169-1191 of bovine IRBP, was shown to be immunodominant by its capacity to stimulate lymphocytes sensitized against whole IRBP. A comparison was made between peptide 1169-1191 and another peptide, 1158-1180, which is nondominant but is immunogenic and immunopathogenic in the Lewis rat. Peptide 1169-1191 was found to be superior in its immunological capacities; the minimal dose of 1169-1191 needed to induce cellular immune response or disease in Lewis rats (0.02-0.1 nmol/rat) is congruent to 1,000 times smaller than that of 1158-1180. In addition, unlike the ocular disease induced by 1158-1180, the disease produced by 1169-1191 resembled that induced by whole IRBP in its kinetics and histopathological features. The immunological activity of 1169-1191 in the Lewis rat was localized to the 10 residues at the COOH terminus; no such activity was exhibited by the truncated peptide 1169-1188, which comprises the 20 residues at the NH2 terminus of the full peptide. The usefulness of this unique experimental system in analyzing the role of immunodominance in peptide immunogenicity and immunopathogenicity is underscored.

Amino Acid Sequence↗