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The effects of perioperative portal venous inoculation with donor lymphocytes on renal allograft survival in the rat. II. Phenotypic and functional analyses of graft-infiltrating cells.

Phenotype, donor-specific cytolytic activity, and helper activity to release cytokines of cells infiltrating within renal allografts of hosts rendered unresponsive by perioperative administration of donor lymphocytes via the portal vein (p.v.) were investigated in order to analyze the mechanism of prolongation of allograft survival. Graft-infiltrating cells (GIC) were obtained from Lewis (LEW, RT-1l) hosts inoculated perioperatively with 1 x 10(8) donor Brown-Norway (BN, RT-1n) lymphocytes p.v., a group that displays prolonged renal allograft survival (MST: 22.2 +/- 5.3 days, n = 10) compared with an uninoculated control group (MST: 7.8 +/- 0.6 days, n = 10, P less than 0.01). The percentages of cytotoxic/suppressor T cells (OX-8+) and Ia-positive cells (OX-6+) in GIC (23.1 +/- 4.4% and 9.0 +/- 2.0%, respectively) and in spleen cells (7.5 +/- 2.6% and 8.5 +/- 1.1%, respectively) from p.v.-inoculated LEW hosts on day 6 postgrafting were significantly lower than those of uninoculated control recipients (GIC: OX-8; 39.4 +/- 8.2%, OX-6; 23.0 +/- 1.9%. SP cell: OX-8; 21.6 +/- 9.9%, OX-6; 12.7 +/- 0.4%, P less than 0.05). Cytolytic activity of GIC from tolerant hosts on day 6 postgrafting toward donor blastoid lymphocytes was significantly decreased (19.0 +/- 1.2% at E/T = 50), compared with that from control allografts during ongoing rejection (51.5 +/- 5.3%, P less than 0.01). The amounts of in vitro cytokine production of GIC from tolerant hosts after mitogen stimulation were remarkably decreased (IL-2: 8.7 +/- 1.4 U/ml, IL-3: 15.4 +/- 0.6 U/ml, and BSF-2: 24.6 +/- 3.5 U/ml) than those of uninoculated control hosts during ongoing rejection (IL-2: 19.6 +/- 2.9 U/ml, IL-3: 22.2 +/- 2.7 U/ml, and BSF-2: 67.5 +/- 13.2 U/ml, P less than 0.05). These results demonstrated that activation of both Tc cells and Th cells was inhibited in the spleen and in situ in renal allografts following administration of donor lymphocytes through the portal vein.

Animals↗

Effect of cold preservation on lymphocyte migration into peripheral nerve allografts in sheep.

Lymphocyte migration into fresh and preserved peripheral nerve allografts was quantitated to assess the effect of cold preservation and freeze-thawing pretreatment on the local immunological response to nerve allografts. Out-bred ewes received multiple 1.5-cm subcutaneous heterotopic peroneal nerve autografts, fresh allografts, and pretreated allografts, implanted within the same recipient. Lymphocyte migration was studied at 7 days by injecting autologous 111indium-labeled lymphocytes intravenously. After 3 hr of recirculation, lymphocyte migration into graft tissue was quantitated by a gamma counter (epm/g, mean +/- SEM). Lymphocyte traffic into fresh nerve allografts (21,623 +/- 3783) increased an average 9.4-fold over the autograft value (2918 +/- 377, P < 0.04). Histologic studies illustrated a marked lymphocytic infiltrate of CD4+ and CD8+ cells and enhanced class I and II MHC expression in fresh allografts, but not in autografts. Short-term cold preservation, for 6 and 12 hr (5 degrees C), enhanced lymphocyte entry into pretreated allograft tissue. Conversely, cold preservation for longer periods (1 and 3 weeks) dramatically reduced lymphocyte migration to values below corresponding autograft levels (783 +/- 100 and 1,252 +/- 120, respectively, P < 0.01). A comparable reduction in lymphocyte migration into nerve allografts was observed after freeze-thawing pretreatment (P < 0.01). Cold preservation of donor allogeneic lymphocytes inhibited their capacity to induce intradermal host lymphocyte migration, implicating passenger lymphocytes as a potential cold-sensitive allogeneic component of the nerve allograft. Assessment of the local response to ovine peripheral nerve allografts, utilizing radiolabeled autologous lymphocytes, demonstrated that cold preservation and freeze-thawing pretreatment significantly reduced lymphocyte migration into nerve allografts. The mechanism(s) of reduced lymphocyte migration may involve inactivation or death of antigen-presenting cells, including passenger lymphocytes.

Animals↗

Production of human alloreactive antibodies by uremic sensitized lymphocytes engrafted in severe combined immunodeficient mice.

BACKGROUND: Numerous studies have documented antibody responses to nominal antigens in human peripheral blood lymphocyte (hu-PBL)-severe combined immunodeficient (SCID) mice engrafted with PBL. We suggest, therefore, that engraftment of SCID mice by allosensitized cells produces alloreactive antibodies (allo-Ab). As such, SCID mice can be used as a model to examine the cellular basis of the sustenance of humoral alloresponses. METHODS: C.B-17 SCID mice were engrafted intraperitoneally with PBL from sensitized uremic patients for 5 weeks and classified into the following: group 1, 8 mice engrafted with unactivated cells (n = 5; n = sensitized patients); group 2, 6 mice engrafted with unactivated PBL (n = 3) followed 2 days later by in vivo activation with interleukin-2 (IL-2) and lipopolysaccharide (LPS); group 3, 11 mice engrafted with cells preactivated in vitro with IL-2 and LPS (n = 6); group 4, 9 mice engrafted with cells preactivated with irradiated allogeneic transformed B cells, IL-2, and LPS (n = 5); group 5, 10 mice engrafted with cells preactivated with IL-2, LPS, and HLA class II allopeptides and adjuvant (n = 6); group 6, 8 control mice engrafted with control cells preactivated with IL-2 and LPS. Two weeks later, each group was rechallenged by the same stimuli. Allo-Ab production was measured by the panel-reactive antibody PRA-STAT ELISA method. Results. Allo-Ab was produced in 54.5% of group 3, 43% of group 4; 80% of group 5, and 0% of groups 1, 2, and 6. The ratio of alloreactive positive wells in the allo-Ab-producing PBL-hu-SCID mice to that present in the respective patient's sera was 82%, 52%, and 87% in groups 3, 4, and 5, respectively. Conclusions. The study demonstrates the feasibility of using the hu-PBL-SCID model to study alloreactive memory B-cell function in humans. Discrete HLA-class allopeptides (group 5) appeared more potent allo-Ab producers than allogeneic cells (group 4).

Adjuvants, Immunologic↗

Patterns of engraftment in different strains of immunodeficient mice reconstituted with human peripheral blood lymphocytes.

BACKGROUND: Models of immunodeficient mice reconstituted with a competent human immune system would represent an invaluable tool for the study of transplantation immunobiology allergy, autoimmunity, and infectious diseases. Severe combined immune deficiency (scid) mice can be successfully reconstituted with human peripheral blood lymphocytes (PBLs), but rates and levels of engraftment are poor. New strains of mice with diverse immunodeficiencies have been recently characterized or developed, which might prove to be advantageous for in vivo studies of human immune reactivity. METHODS: We have compared rates and patterns of human PBL engraftment in four available immunodeficient murine strains; scid-beige, nonobese diabetic (NOD)-scid, NOD-scid-beta2 m- and rag-. T- and B-lymphocyte engraftment, phenotype of engrafted cells, and occurrence of graft-versus-host disease (GVHD) were studied and compared. RESULTS: Successful engraftment of human PBL was readily obtained in the majority of scid-beige, NOD-scid, and NOD-scid-beta2 m- with a single i.p. administration of human PBLs, whereas it was seldom achieved in rag- animals. Human Ig levels were accordingly remarkably low in rag- recipients but, interestingly also in NOD-scid-beta2 m- mice. Engraftment was readily observed not only in peripheral blood but also in spleen and bone marrow of successfully reconstituted animals. Phenotypic analysis of engrafted human cells showed preserved CD4/CD8 ratios and a clear skewing toward an activated phenotype. GVHD was invariably observed in successfully reconstituted animals. CONCLUSIONS: Our data indicate that a high rate of reconstitution with human lymphocytes can be achieved in scid-beige, NOD-scid, and NOD-scid-beta2 m- mice. Human Ig are produced at high levels, except in NOD-scid-beta2 m-, including xenoreactive natural antibodies. Scid-beige and NOD-scid appear therefore better suited than NOD-scid-beta2 m- or rag- for analysis of human immunoreactivity in vivo. An important caveat is the invariable occurrence of GVHD that precludes long-term studies in this model system.

Animals↗

B7/CTLA4 pathway is essential for generating regulatory cells after intratracheal delivery of alloantigen in mice.

BACKGROUND: The mechanism of hyporesponsiveness induced by intratracheal (IT) delivery of alloantigen was examined and its effect on cardiac graft survival was assessed in studies in mice. METHODS: In CBA (H2 ) mice, donor splenocytes were given by IT delivery 7 days before transplantation of a C57BL/10 (H2 ) heart. To determine whether regulatory cells were involved in hyporesponsiveness, splenocytes from mice given IT delivery of alloantigen and antibodies for B7-1, B7-2, or CTLA4 were adoptively transferred to naïve secondary recipients 7 days after delivery; those recipients underwent heart transplantation the same day. Effects on cell proliferation and cytokine production of splenocytes from mice given IT delivery of alloantigen were examined in mixed leukocyte cultures (MLC). RESULTS: Cardiac graft survival was significantly prolonged in mice given IT delivery of alloantigen (median survival time [MST], 81 days); those given syngeneic splenocytes rejected grafts acutely (MST, 7 days; P<0.05). Adoptive transfer of splenocytes also significantly prolonged survival of cardiac grafts in secondary recipients (MST, 62 days). When B7-1, B7-2, or CTLA4 antibody was combined with IT delivery of alloantigen in the first recipient, all grafts were rejected within 14 days in second recipients after adoptive transfer. In mixed leukocyte cultures, splenocytes from these mice did not respond to alloantigen and production of interleukin-4 and interleukin-10 was increased. CONCLUSIONS: Donor splenocytes delivered IT induced hyporesponsiveness and regulatory cells in our animal model, and such induction was dependent on B7-1, B7-2, and CTLA4 signals.

Abatacept↗

Engineered lymphocytes to treat dinitrobenzene sulphonic acid colitis in mice.

Current treatments of inflammatory bowel diseases are limited either by their lack of efficacy or their potential toxicity. In recent years, major advances have been obtained by the development of biological therapies. However, these types of treatment are systemic and can lead to serious adverse events. The new venue of local biological treatments would be most welcome. In this issue of the Journal, Castagliuolo et al. show that lymphocytes engineered to produce TGF-beta1 can reverse dinitrobenzene sulphonic acid-induced colitis in mice. These engineered lymphocytes selectively accumulate in the intestinal mucosa due to the homing properties of their alpha4beta7 integrins, a ligand for MAdCAM1. A local treatment restricted to the inflamed mucosa can thus be obtained. This opens a brand new area of research with the hope of restoring the immunoregulatory balance selectively in the inflamed tissues.

Animals↗

Lymphocytes endowed with colon-selective homing and engineered to produce TGF-beta1 prevent the development of dinitrobenzene sulphonic acid colitis.

BACKGROUND: Gene therapy is an attractive approach to the treatment of inflammatory diseases. However, the lack of tissue targeting of available vectors jeopardizes their clinical use. AIMS: Since alpha4beta7 integrin mediates lymphocyte homing to the intestinal mucosa, we tested the possibility of in-vitro engineering alpha4beta7-bearing lymphocytes to restrict the production of a therapeutic cytokine, transforming growth factor (TGF)-beta1, to within the colonic mucosa. METHODS: Lymphocytes were isolated from colonic lamina propria or spleen and transfected with either pC1 or pC1/TGF-beta1. RESULTS: Transfected spleen and lamina propria cells released TGF-beta1 for up to 5 days in vitro and administration of 107 spleen cells, but not 106 lamina propria or spleen cells, to normal mice caused a significant rise in circulating TGF-beta1. Following intrarectal injection of dinitrobenzene sulphonic acid, intraperitoneal administration of lamina propria or spleen cells transfected with pC1/TGF-beta1, but not pC1, significantly reduced colitis-associated body weight loss, colonic myeloperoxidase (MPO) activity, interleukin-1beta levels, and macroscopic and microscopic inflammatory damage. Vector-specific TGF-beta1 mRNA transcripts were detectable in the colon and liver following injection of lamina propria lymphocytes, and in the spleen, liver and colon following administration of spleen lymphocytes. Incubation of pC1/TGF-beta1-transfected lamina propria lymphocytes with anti-alpha4beta7 integrin antibody blocked their protective effects and caused the disappearance of vector-specific TGF-beta1 transcripts from the colonic mucosa. CONCLUSION: We conclude that lymphocytes are an efficient vehicle for transient gene therapy and that cells bearing alpha4beta7 integrins preferentially deliver therapeutic genes to the colonic mucosa.

Animals↗

Combined RT-PCR and metaphase-FISH posttransplant studies in pediatric patients with chronic myeloid leukemia.

PURPOSE: To evaluate the use of a combined reverse-transcriptase polymerase chain reaction (RT-PCR) and metaphase fluorescent in situ hybridization (FISH) approach post-allogeneic marrow transplant in the detection of relapse in pediatric patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Five pediatric patients with CML were monitored post-allogeneic transplant (two of them also had received donor lymphocyte infusions) using the combined approach of RT-PCR and metaphase FISH. Both the transplants and the follow-up were carried out in a single institution setting. RESULTS: During the posttransplant evaluation, a transiently positive signal for the Philadelphia chromosome but no transcription of the bcr/abl-fusion message was detected in one patient currently in remission. A posttransplant relapse was detected in two patients who demonstrated the Philadelphia chromosome and the bcr/abl-fusion transcript; one was successfully treated with donor lymphocyte infusions. The two patients consistently negative for both the Philadelphia chromosome and the bcr/abl-fusion transcript and currently in remission. CONCLUSION: Pediatric patients with CML may transiently demonstrate cells positive for the Philadelphia chromosome but not actively transcribing the bcr/abl-fusion message in their marrow during their posttransplant evaluation but remain in remission. Recurrence is highly likely in patients demonstrating positivity for both; these patients may be considered candidates for donor lymphocyte transfusion therapy.

Adolescent↗

Local and systemic desensitization induced by repeated epicutaneous hapten application.

Frequent skin exposure of guinea pigs to the contact sensitizing agents dinitrochlorobenzene or 4-ethoxymethylene-2-phenyloxazolone induced both systemic hyposensitization and local unresponsiveness within 8 weeks. Both phenomena were hapten-specific. Decreased systemic reactivity in repeatedly painted guinea pigs is probably not due to receptor blockade or the development of hapten-specific antibodies, but rather to transient sequestration of hapten-specific effector cells within lymph nodes draining the site of hapten exposure. After discontinuation of allergen exposure, effector cells return into the circulation, as indicated by a reversal of systemic hyporesponsiveness within 5 weeks. The persistence of a cellular infiltrate at the site of repeated application and the hapten-specific unresponsiveness at this site suggest that suppressor cells play a role in local unresponsiveness. Upon discontinuation of allergen exposure, local unresponsiveness rapidly dissolves (within one week). Since the circulation is still depleted of effector cells, residual hyporesponsiveness may persist for longer periods.

Administration, Topical↗

Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes.

MRL/l mice develop progressive, virulent autoimmune disease that has many of the features of systemic lupus erythematosus. Prophylactic treatment of MRL/l mice with syngeneic photoinactivated autoimmune splenocytes improves survival and inhibits the fulminant hyperproliferation of abnormal T cells and the production of high titer anti-DNA antibody invariably found in untreated mice. The proliferation of Thy 1+ splenic T cells was significantly decreased, and prolonged retention of the response to T-cell mitogen was found in treated mice. Treatment with unmodified cells induced a partial inhibition of disease features which did not prolong survival rates. These results suggest that phototherapy potentiates a normal immunoregulatory process which enables suppression of the development of abnormal cell populations in young MRL/l mice with relatively intact immune systems.

Animals↗

Immune reconstitution in the immunodeficient chicken by transfer of embryonic lymphoid cells.

Embryonic chickens were rendered immunodeficient by in ovo injection of homologous IgM on the 10th embryonic day. The immunodeficient embryos were intravenously given lymphoid cells taken from normal embryonic bursa, spleen or thymus on the 15th embryonic day. Gain of splenic or bursal weight, natural antibodies to sheep red blood cells (SRBC), frequencies of rosette forming cells (RFC) binding to SRBC or dinitrophenyl-SRBC (DNP-SRBC) and of immunoglobulin bearing cells (IBC) in the bursa and the spleen were investigated to assess the effect of transferred cells during the embryonic stage. Transferred bursal and splenic cells showed an ability to restore the frequency of RFC or IBC in the recipients. However, reversion from the immunodeficient state was not observed in the thymic cell transfer. These findings suggested that the cells derived from embryonic bursa and spleen contained stem cells which developed into RFC and also into precursors of IBC.

Animals↗

Tolerance induction of alloreactivity by portal venous inoculation with allogeneic cells followed by the injection of cyclophosphamide. II. Cellular and molecular mechanisms underlying tolerance.

BALB/c mice receiving allogeneic C3H/He or C57BL/6 spleen cells via portal venous (p.v.) route or a single administration of cyclophosphamide (Cy) were capable of rejecting the respective allogeneic C3H/He- or C57BL/6-derived tumor cells. In contrast, the combined treatment of p.v. inoculation with allogeneic lymphocytes and Cy administration abrogated the capability of rejecting allogeneic tumor cells. Such abrogation of alloreactivity was alloantigen-specific and associated with the suppression of potentials to generate delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses to alloantigens. This was further substantiated by the inhibition of molecular mechanisms underlying anti-allo-DTH and -CTL responses. Thus, the above combined treatment led to the decreased production of lymphokines such as macrophage-activating factor (MAF) and interleukin 2 (IL2) following the stimulation with the relevant alloantigens. These results demonstrate that p.v. inoculation of allogeneic cells followed by a single administration of Cy results in the effective elimination of alloreactivity as verified by the suppression of cellular and molecular mechanisms of alloreactive responses.

Animals↗

The development and specificity of cytotoxic cells in cattle immunized with autologous or allogeneic Theileria annulata-infected lymphoblastoid cell lines.

Two groups of animals were immunized with either 10(6) autologous or 10(6) allogeneic Theileria annulata-infected lymphoblastoid cells cultured in vitro. The development and specificity of cytotoxic cells generated in vivo were measured throughout immunization and challenge using a panel of target cells that were either Theileria-infected or uninfected blast cells of known bovine lymphocyte antigen (BoLA) specificities. After inoculation of the cell lines the two groups showed distinct differences in both their clinical responses and the target specificity of the cytotoxic cells detected. The allogeneic T. annulata cell line recipients showed a very mild clinical response, and on day 9 after inoculation a strong cytotoxic response was detected. The response appeared to be directed against the allogeneic major histocompatibility complex (MHC) antigens of the inoculated cell line in some form of graft rejection response. By day 23 the predominant cytotoxic response was directed against the recipient animals' own cells infected with the parasite. In contrast, the autologous T. annulata cell line recipients showed very severe clinical reactions, and low levels of cytotoxicity were detected. The cytotoxicity was directed against parasite-infected targets but did not appear to be MHC restricted until day 20. Both groups were immune to a heterologous sporozoite challenge that proved lethal to two susceptible control animals, and on day 10 after challenge a peak of cytotoxicity was detected which was directed against the autologous infected target cell. This would suggest that this cytotoxic response was MHC restricted and was also cross-reactive between the heterologous parasite stocks used.

Animals↗

Specifically decreased MLC response of lymphocytes from CBA mice injected with cells from the H-2-compatible, M-antigen-incompatible strain C3H. Lack of such effect after injection of H-2-disparate C3H-hybrid cells.

The mixed lymphocyte culture (MLC) response of lymphocytes from CBA mice against C3H cells was studied after injection of spleen cells from C3H mice or C3H hybrids. Intravenous infusion of C3H cells resulted in a strongly suppressed specific MLC response, but this was not the case when cells from H-2-incompatible hybrids of C3H mice were injected. However, when mixtures of cells from the two parental strains--C3H cells and H-2-incompatible cells--were injected into CBA mice, there was a strongly suppressed MLC response to C3H cells. Mice that were hybrids between CBA and an H-2-disparate strain showed a depressed MLC response against C3H after injection of cells from hybrids between C3H and the same H-2-disparate strain. The results may indicate that a suppression of the MLC response to the strongly stimulatory non-H-2 antigen on C3H lymphocytes develops only when the immunizing cells can survive in the host for long periods, thus exhausting the pool of specifically responsive cells. The presence of another foreign transplantation antigen, such as H-2, on the same cells shortens the survival of the cells in the recipient.

Animals↗

Enzymatic modification of lymphocyte receptors for antigen III. loss of antigen-responsiveness with recovery after adoptive transfer.

Spleen cells from bovine serum albumin (BSA)-primed CBA mice were exposed to proteolysis by papain and pronase under conditions where cell recovery and viability were not impaired but surface Ig and antigen-binding were greatly reduced. The ability of the cells to respond to BSA was tested by a modified Farr assay of serum taken 10 days after adoptive transfer of cells to lethally irradiated syngeneic recipients. Cells not exposed to enzymes were able to respond to BSA either in vitro before adoptive transfer or in vivo after transfer. Cells exposed to papain and pronase were unable to respond in vitro, but normal antibody production was approached when the cells were exposed to antigen in vivo. Thus, after removal of much surface Ig the cells were temporarily unresponsive to antigen but were still functional, as demonstrated by their ability to recover responsiveness in vivo.

Animals↗

Reduced capacity to produce specific 'effector' cells after injection of CBA mice with C3H cells.

Lymphocytes from mice of strain CBA are strongly MLC-responsive to lymphocytes from the H-2-compatible but M-antigen-incompatible strain C3H. This strong reactivity disappears after infusion of CBA mice with C3H lymphocytes. This study shows that the host-versus-graft reactivity (swelling of local lymph node after antigen injection) is specifically reduced after injection of CBA mice with C3H times CBA spleen cells. However, lymphocytes from such mice showed a specifically increased GVH reactivity (inhibition of erythroid cell growth) compared with lymphocytes from unimmunized mice. Lymphocytes from normal CBA mice showed a high proliferative rate in the spleens of irradiated C3H times CBA mice. Such 'educated' cells showed strongly increased specific GVH reactivity. Lymphocytes from CBA mice previously injected with C3H times CBA cells showed reduced capacity to proliferate when injected into irradiated C3H times CBA hybrids and a poor capacity to develop new 'effector' cells reactive against C3H times CBA bone marrow target cells. The results indicate that the presence of specifically 'MLC-responsive' lymphocytes in a lymphoid cell population is a prerequisite of its production of 'effector' cells able to respond in this GVH assay.

Animals↗

Stimulation of normal lymphocytes with autologous lymphoid cell lines: properties of derived killer cells.

Lymphocytes from normal adults, with or without serological signs of previous Epstein-Barr virus (EBV) infection, could be stimulated to proliferate and produce killer cells by incubation with autologous EBV-genome-positive lymphoid cell lines (LCLs). The stimulated cells were most probably of T-cell origin, although at the peak of stimulation many of them lacked the sheep erythrocyte marker. Direct effector-target cell contact was necessary for lysis to occur. The cytotoxicity of autologously stimulated (AS) lymphocytes was not restricted to EBV-genome-positive LCLs, nor to cell lines of hematopoietic origin. It was equally broad if cells carrying complement receptor had been removed before stimulation. Fresh lymphocytes, blasts induced by phytohemagglutinin or concanavalin A, and Burkitt's lymphoma biopsy cells were resistant or considerably less sensitive. Mouse cells--even cell lines--were resistant. The sensitivity of target cells to lysis correlated positively with their capacity to block AS lymphocyte lysis of autologous LCLs in competition experiments. The cytotoxicity of AS lymphocytes was blocked by EBV-genome-positive and -negative cell lines, whereas the EBV-related cytotoxicity of T cells from acute cases of infectious mononucleosis was blocked by EBV-genome-positive LCL only.

Animals↗

Complex nature of the production of 'effector' cells and their interaction with target cells in the M-antigen system of the mouse.

The capacity of lymphocytes from mouse strain CBA to generate 'effector' cells against the H-2-compatible, M-antigen-incompatible strain C3H and their interaction with such target cells were investigated. It was observed that CBA lymphocytes injected in, and 5 days later obtained from, the spleens of irradiated C3H X CBA hybrids ('educated cells') could strongly inhibit the growth of C3H X CBA bone marrow cells but were almost nonresponsive to C3H X C57BI bone marrow targets (H-2-incompatible). CBA lymphocytes educated in irradiated C3H X C57BI hosts displayed reactivity against C3H X C57BI and CBA X C57BL but not against C3H X CBA bone marrow target cells. Additional tests indicated that the M antigen determined by C3H is expressed to approximately the same extent on C3H X CBA and C3H X C75BL cells and that the M antigen on C3H does not cross-react immunologically with antigens on C57BL cells. Moreover, it was observed that CBA X C57BI lymphocytes were triggered to cell proliferation by C3H antigens but were unable or had a highly reduced capacity to develop 'effector' cells in response to this antigenic stimulus. These results indicate that generation of 'effector' cells and their interaction with target cells are very complex processes.

Animals↗