Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma

The generation of murine monoclonal antibodies reactive with human leukemia and lymphoma cells has recently led to clinical trials that have begun to evaluate the use of these reagents in the treatment of various leukemias and lymphomas. Several of these studies have demonstrated that infusion of monoclonal antibody can cause the rapid and specific clearance of leukemic cells from the peripheral blood. Intravenously administered antibody also rapidly binds to bone marrow lymphoblasts, and in one instance, has resulted in the partial regression of tumor cell infiltrates in lymph nodes and skin. Unfortunately, clinically significant responses have not in general been achieved, but these clinical studies have identified specific factors that result in the development of resistance to antibody- mediated lysis in vivo. These factors include the presence of circulating antigen, antigenic modulation, reactivity of monoclonal antibody with normal cells, immune response to murine antibody, and the inefficiency of natural immune effector mechanisms. Current research is now being directed towards developing methods to circumvent each of these obstacles. Future clinical studies utilizing antibodies in vitro or with different specificity may demonstrate greater therapeutic efficacy. In addition, monoclonal antibodies can be used as carriers of other cytotoxic agents and in conjunction with other agents that will reduce the total load. Monoclonal antibodies represent new and powerful reagents that may in the near future become an additional therapeutic modality for patients with malignant disease.     

Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3

We investigated the mechanism by which antihuman CD3 monoclonal antibodies of the isotypes IgG2a (eg, OKT3) and IgA (eg, IXA) can induce the rapid disappearance of virtually all circulating T lymphocytes. We hypothesize that upregulation of adhesion molecules on the lymphocyte membrane contributes to this effect. However, this hypothesis is difficult to test, because of the inherent lymphocytopenia and/or shifts in lymphocyte populations between intra and extra-vascular compartments. Therefore, studies in vitro were performed, as well. Analysis of peripheral blood lymphocytes isolated at several times after addition of OKT3 or IXA to whole blood of healthy individuals showed an immediate increase in the proportion of T cells expressing NKI-L16, an activation epitope on CD11a/CD18. Likewise, an increase in CD11b/CD18 expression occurred. In parallel experiments, a transiently increased adhesion of T cells to endothelial cell monolayers was observed. This adhesion could be completely blocked by anti-CD18 or anti-CD11a monoclonal antibodies and only partly by an anti-CD11b antibody. Our data indicate that upregulation of activation epitopes of CD11a/CD18, as well as increased expression of CD11b/CD18 on T lymphocytes, may result in increased adhesion of these cells to intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on vascular endothelium. This phenomenon may, at least, partly explain the rapidly occurring peripheral lymphocytopenia observed in vivo.     

Intravenous or cold ex vivo administration of monoclonal antibodies for conditioning of rat small-bowel allografts

The following study describes cold ex vivo or intravenous infusion of monoclonal antibodies (MCAB) for lymphocyte target cells of rat small-bowel grafts. The MCAB Ox8, directed against CD8+ T lymphocytes, is used here as a model antibody. We demonstrate that Ox8 antibodies administered during cold ex vivo perfusion are able to reach the target cells in the small-bowel mucosa and the mesenteric lymph nodes of rat small-bowel grafts. Thus, cold perfusion of the vascular system for 20-60 min resulted in good labelling of the CD8+ T cells as analysed on cryostat tissue sections using immunoperoxidase staining. Rats treated with Ox8 intravenously 60 min before taking of specimens showed similar labelling. Additional staining of the tissue sections with Ox8 antibody resulted in no further labelling, thus indicating that nearly all CD8+ T cells were labelled both after ex vivo perfusion and after intravenous treatment of the donor. It is concluded that MCAB can, as an alternative to the intravenous route, be administered ex vivo after organ harvesting.     

Limited contribution of humoral immunity to the clearance of measles viremia in rhesus monkeys

The development of an improved vaccine for controlling measles virus (MV) infections in the developing world will require an understanding of the immune mechanisms responsible for the clearance of this virus. To evaluate the role of humoral immunity in the containment of MV, rhesus monkeys were treated at the time of MV challenge with either anti-CD20 monoclonal antibody (MAb) infusion, to deplete B lymphocytes, or both anti-CD20 and anti-CD8 MAb, to deplete both B lymphocytes and CD8+ effector T lymphocytes. Although the MV-specific antibody response in CD20+ lymphocyte-depleted monkeys was delayed by >1 week, the kinetics of MV clearance did not differ from those for monkeys that received control MAb. Furthermore, unusual clinical sequelae of MV infection were not observed in these monkeys. In contrast, MV-infected rhesus monkeys depleted of both CD20+ and CD8+ lymphocytes had a prolonged duration of viremia and developed a desquamating skin rash. These findings indicate that humoral immunity plays a limited role in the control of MV replication in an MV-naive individual and suggest that new measles vaccination strategies should focus on the elicitation of cell-mediated immune responses, in addition to neutralizing antibodies, to facilitate rapid elimination of locally replicating virus.     

Expression patterns of phenotypic markers on lymphocytes from human immunodeficiency virus type 2-infected baboons

The development of AIDS in HIV-1-infected humans is associated with profound changes in the expression patterns of lymphocyte phenotypic markers associated with increased immune activation and with decreased recall immune responses. In assessing these immunologic changes in an animal model, we characterized the expression patterns of immune activation markers on lymphocyte subsets during the acute, chronic, and end stages of HIV-2 infection in baboons. Using flow cytometry, we identified 21 human-specific monoclonal antibodies that were cross-reactive with baboon lymphocytes; however, expression of only 2 of these markers was altered significantly after HIV-2 infection. We found an increase in baboon class II antigen (as measured by anti-HLA-DR) in the CD4(+) T cell subset within 8 weeks of infection (p = 0.045). Moreover, after 1 year of infection, CD11b was downregulated on CD8(+) T lymphocytes (p = 0.027). This downregulation of CD11b was consistently observed in all of the groups of baboons that were chronically infected with three different HIV-2 isolates. In addition, we found substantial downregulation of the interleukin 2 receptor (CD25) and upregulation of class II antigen on CD8(+) lymphocytes in a baboon with an AIDS-like disease. These and other phenotypic markers of immune activation may facilitate characterization of the immunopathogenesis of AIDS in nonhuman primate animal models.     

Monoclonal antibodies in the treatment of cancer

Potential uses of monoclonal antibodies in anti-cancer treatment include passive serotherapy, radioisotope conjugates, toxin-linked conjugates, and chemotherapy-monoclonal antibody conjugates. The bases for these applications have been founded in research with heterologous antisera, and in some cases with monoclonal antibodies in animal tumor models. Human trials with passive serotherapy have already begun in both hematopoietic and solid tumor malignancies. Promising results have been reported in cutaneous T cell lymphoma with anti-T cell monoclonal antibody, and in nodular lymphoma with anti-idiotype monoclonal antibody. Radioisotope conjugate work appears promising for imaging in both animals and humans, and this work will lay the foundation for possible therapeutic application of radio-immunotherapy. Toxin-linked conjugates are promising in vitro and may have application in autologous bone marrow transplantation. Research with chemotherapy conjugates is also underway. Preliminary results suggest that murine monoclonal antibodies will be well tolerated clinically except in the setting of circulating cells which bear the target antigen, where rapid infusions may be associated with intolerable side effects. In certain diseases, production of endogenous anti-mouse antibodies may also limit application. Advances in the technology for human-human hybridoma production may help solve some of these problems.     

Studies on the use of nonhuman primates to determine the DR status of the human hematopoietic stem cell

Monoclonal antibodies that recognize monomorphic determinants of human DR are potentially useful for the in vitro elimination of malignant cells from marrow for use in autologous transplantation. While DR is expressed on normal hematopoietic progenitor cells and the cells of the majority of the hematologic and lymphoid malignancies, there is the possibility that DR may not be expressed on the hematopoietic stem cells responsible for marrow regeneration after transplantation. To resolve the uncertainty regarding the DR status of the human stem cell, we determined whether antihuman DR monoclonal antibodies recognized analogous antigens on nonhuman primate hematopoietic progenitor cells to determine an appropriate animal transplant model. We used antihuman DR plus C'-mediated lysis of marrow progenitor cells as an indicator of whether the analogous nonhuman primate cells express similar antigens. Using two potent C'-fixing anti-DR monoclonal antibodies separately (5F3, AMG-12), human progenitor cells are reduced by 90%-100%. The range of progenitor cell depletion varied more widely with the nonhuman primates studied: 80%-99% with cells from the chimpanzee, 48%-100% with cells from the orangutan, and 62%-100% with cells from the rhesus monkey. Despite this, the majority of animals yielded results identical to that seen with human cells. We concluded that autologous transplantation with DR-depleted rhesus bone marrow into a lethally irradiated animal would be a practical and expeditious means to determine the DR status of the cell responsible for marrow regeneration, and by inference the DR status of the human hematopoietic stem cell.     

Search for CEA-like molecules in polymorphonuclear leukocytes of non-human primates using monoclonal antibodies

The monoclonal anti-CEA antibody ZIK-A42-A/C1 which reacts with NCA of human polymorphonuclear leukocytes was found to bind also to polymorphonuclear blood leukocytes of the following non-human primates tested: hamadryas baboon (Papio hamadryas), stump-tailed monkey (Macaca arctoides), pig-tailed monkey (Macaca nemestrina), and rhesus monkey (Macaca mulata). No binding was observed to mononuclear blood leukocytes. It was concluded that non-human primates contain CEA-like substances in their polymorphonuclear leukocytes as humans do and that these substances carry some identical epitopes.     

Murine monoclonal antibody therapy in two patients with chronic lymphocytic leukemia

We infused the murine monoclonal antibody T101 into two patients with advanced refractory chronic lymphocytic leukemia (CLL) after confirming its reactivity with their CLL cells. One patient received doses of 1, 3, and 12 mg; the second patient received 10 mg. Antibody was delivered over 10--15 min. The major observations were: (1) T101 murine monoclonal antibody did bind to cells with T65 surface antigen and saturated these cells in vivo; (2) cells that bound T101 disappeared from the circulation by 2 hr after treatment, as evidenced by a marked drop in lymphocyte counts; (3) T101 serotherapy resulted in some intravascular cell injury associated with sequestration and probably destruction in the liver and lung; (4) free serum T101 was demonstrable, but disappeared by 2--4 hr after infusion; (5) rapid infusion of T101 did not induce significant modulation of T65; (6) rapid infusion of greater than 10 mg of T101 was associated with significant systemic reactions. Monoclonal antibodies may someday have an application in leukemia therapy, but additional experimental trials are clearly indicated.     

Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys.

Although systemic virus-specific cytotoxic T lymphocyte (CTL) responses are of critical importance in controlling virus replication in individuals infected with human immunodeficiency virus 1 (HIV-1), little is known about this immune response in the gastrointestinal (GI) tract. This study investigated the GI tract CTL response in a nonhuman primate model for HIV-1 infection, simian immunodeficiency virus (SIV)-infected rhesus monkeys. Lymphocytes from duodenal pinch biopsy specimens were obtained from 9 chronically SIVmac-infected rhesus monkeys and GI tract lymphocytes were harvested from the jejunum and ileum of 4 euthanized SIVmac-infected rhesus monkeys. Lymphocytes were also assessed in GI mucosal tissues by in situ staining in histologic specimens. SIVmac Gag-specific CTLs were assessed in the monkeys using the tetramer technology. These GI mucosal tissues of chronically SIVmac-infected rhesus monkeys contained levels of CTLs comparable to those found in the peripheral blood and lymph nodes. The present studies suggest that the CD8(+) CTL response in GI mucosal sites is comparable to that seen systemically in SIVmac-infected rhesus monkeys.     

Induction and enhancement by monocytes of antibody-induced modulation of a variety of human lymphoid cell surface antigens

We have previously reported that the addition of monocytes results in enhanced modulation of the T65 antigen when normal or leukemic lymphoid cells were cultured in vitro with the T101 monoclonal antibody. In the present investigation, we extend these findings to demonstrate that monocyte-enhanced modulation is a phenomenon that occurs with a variety of T and B lymphoid antigens identified by murine monoclonal antibodies. Two patterns of monocyte-enhanced modulation were observed: (1) augmentation by monocytes of existing antigen modulation by the T101 and anti-Leu-4 antibodies, and (2) induction by monocytes of previously unrecognized modulation with the anti-Leu-2 and anti-Leu-9 antibodies. Enhancement of modulation by monocytes was also detected with antibodies to surface IgM and HLA-DR antigens. Antigen modulation on lymphoid cell lines appeared to be more variable than on fresh cells, with or without monocytes. Monocyte-enhanced antigen modulation was not demonstrated with two monoclonal antibodies against solid tumors. Monocyte-enhanced modulation was shown to be dependent upon the Fc portion of the antibody, but independent of proteolytic or oxidative compounds released by monocytes. These findings indicate that the results obtained during in vitro studies of antigen modulation may vary with the source of cells and the extent to which monocytic cells are present. In addition, these findings suggest an enhanced role for Fc receptor-bearing cells of monocytic origin in antigen modulation following in vivo administration of monoclonal antibodies.     

Surface antigen specificity of cold-reactive IgM antilymphocyte antibodies in systemic lupus erythematosus

Monoclonal antibodies to known surface antigens on B cells and on resting and activated T cells of various types were used in several approaches to examine the specificity of IgM antilymphocyte antibodies in systemic lupus erythematosus (SLE). Surface determinants that were sought included: T3, T11, Leu-1, Leu-8 (pan-T); T4, T8 (T subset); beta 2-microglobulin (beta 2m); L243, Leu-10 (DR and DS/DC framework, respectively); anti-Tac (interleukin-2 receptor); 5E9 (transferrin receptor); and 4F2, AA1 (other activation antigens). The first strategy was based on inhibition of rosette formation between mouse monoclonal antibody-coated targets and anti-mouse IgG-coated erythrocytes by SLE sera, either directly at 4 degrees C or after modulation of IgM antilymphocyte antibody-reactive target cell antigen at 37 degrees C. Significant rosette inhibition, defined as greater than 2 standard deviations from the mean value for 10 control sera, was seen only for beta 2m (13 of 20 SLE sera were positive; inhibition = 15-58%). Next, relative fluorescence intensity of lymphocyte staining by monoclonal antibodies was assessed by flow microfluorometry after preincubation of cells with SLE serum at 4 degrees C or after modulation of SLE antibody-reactive antigen. Modulation markedly reduced or eliminated SLE antilymphocyte antibody IgM staining. Except for beta 2m, neither cold nor warm temperature preincubations altered the relative fluorescence intensity for the known surface antigens. These data confirm anti-beta 2m as a common antibody specificity in SLE and suggest that antilymphocyte antibodies in this disorder are not directed to Ia or to certain other defined lymphocyte antigens of functional interest.     

In vivo marking of rhesus monkey lymphocytes by adeno-associated viral vectors: direct comparison with retroviral vectors.

We have compared adeno-associated virus (AAV)-based and retrovirus-based vectors for their ability to transduce primary T lymphocytes in vitro and then tracked the persistence of these genetically marked lymphocytes in vivo, using the rhesus monkey model. To avoid the complication of immune rejection of lymphocytes transduced with xenogeneic genes in tracking studies primarily designed to investigate transduction efficiency and in vivo kinetics, the vectors were designed without expressed genes. All vectors contained identically mutated beta-galactosidase gene (beta-gal) and neomycin resistance gene (neo) DNA sequences separated by different length polylinkers, allowing simple differentiation by polymerase chain reaction (PCR). Each of 2 aliquots of peripheral blood lymphocytes from 4 rhesus monkeys were transduced with either AAV or retroviral vectors. The in vitro transduction efficiency (mean vector copy number/cell) after the ex vivo culture was estimated by PCR at 0.015 to 3.0 for AAV, varying depending on the multiplicity of infection (MOI) used for transduction, and 0.13 to 0.19 for the retroviral transductions. Seven days after transduction, Southern blot analysis of AAV-transduced lymphocytes showed double-stranded and head-to-tail concatemer forms but failed to show integration of the AAV vector. AAV and retroviral aliquots were reinfused concurrently into each animal. Although the retrovirally marked lymphocytes could be detected for much longer after infusion, AAV transduction resulted in higher short-term in vivo marking efficiency compared with retroviral vectors, suggesting possible clinical applications of AAV vectors in lymphocyte gene therapy when long-term vector persistence is not required or desired.     

Inhibition of specific cell-mediated cytotoxicity by monoclonal antibodies to human T cell antigens

Human T lymphocyte subpopulations recently have been defined by monoclonal antibodies that recognize cell-surface antigens selectively expressed on functionally distinct T cell subsets. The majority (approximately 90%) of the peripheral blood sheep erythrocyte-rosette-forming cells carry the OKT3 antigen. Helper cells are OKT4⁺, whereas cytotoxic/suppressor cells are OKT5⁺ and OKT8⁺. We investigated the effect of several monoclonal antibodies recognizing T cell antigens on certain proliferative responses of T cells and on the effector phase of the specific T cell-mediated cytotoxicity generated in mixed lymphocyte culture (MLC). In the absence of added complement, (i) OKT3 and OKT4 monoclonal antibodies inhibited the proliferative response to phytohemagglutinin (PHA), (ii) OKT3 monoclonal antibody inhibited the proliferative response to allogeneic cells in MLC, and (iii) OKT3 monoclonal antibody significantly and regularly inhibited the effector phase of the specific T cell-mediated cytotoxicity against allogeneic targets (P < 0.001) in a concentration-dependent manner. The OKT5 and OKT8 monoclonal antibodies, again in the absence of complement, inhibited moderately the specific cell-mediated cytotoxicity. This inhibition was observed in some experiments only. Inhibition of the specific cytotoxicity by these antibodies also was observed in secondary responses. In contrast, again in the absence of added complement, none of these antibodies had an effect on the nonspecific cytotoxicity generated in MLC against the K562 targets. The OKT4 antibody in the absence of added complement had no effect on either the specific or nonspecific cytotoxicity. Furthermore, treatment with OKT3 or OKT8 antibody and complement completely abrogated the specific T cell-mediated cytotoxicity but had no effect on the natural killer-like cytotoxicity against the K562 cells. Treatment with the OKT4 antibody and complement had no effect. These results suggest that (i) the T5/T8 and T3 antigens, present on cytotoxic T lymphocytes, may be involved directly or indirectly in the antigen recognition step(s) or the lytic mechanism of T cell-mediated lympholysis; and (ii) nonspecific cytotoxicity against the K562 targets generated in MLC is mediated by cells phenotypically different than those that mediate specific cytotoxicity.     

Nonhuman primates as models for human adrenal androgen production: Function and dysfunction

The origin of circulating DHEA and adrenal-derived androgens in humans and nonhuman primates is largely distinct from other mammalian species. In humans and many Old world primates, the fetal adrenal gland and adult zona reticularis (ZR) are known to be the source for production of DHEA (and DHEAS) in mg quantities. In spite of similarities there are also some differences. Herein, we take a comparative endocrine approach to the diversity of adrenal androgen biosynthesis and its developmental timing in three primate species to illustrate how understanding such differences may provide unique insight into mechanisms underlying adrenal androgen regulation and its pathophysiology in humans. We contrast the conventional developmental onset of adrenal DHEA biosynthesis at adrenarche in humans with (1) an earlier, peri-partutrition onset of adrenal DHEA synthesis in rhesus macaques (Old World primate) and (2) a more dynamic and reversible onset of adrenal DHEA biosynthesis in female marmosets (New World primate), and further consider these events in terms of the corresponding developmental changes in expression of CYP17, HSD3B2 and CYB5 in the ZR. We also integrate these observations with recently described biochemical characterization of CYP17 cDNA cloned from each of these nonhuman primate species and the corresponding effects of phosphorylation versus CYB5 coexpression on 17,20 lyase versus 17-hydroxylase activity in each case. In addition, female rhesus macaques exposed in utero to exogenous androgen excess, exhibit symptoms of adrenal hyperandrogenism in adult females in a manner reminiscent of that seen in the human condition of PCOS. The possible mechanisms underlying such adrenal hyperandrogenism are further considered in terms of the effects of altered relative expression of CYP17, HSD3B2 and CYB5 as well as the altered signaling responses of various kinases including protein kinase A, or the insulin sensitive PI3-kinase/AKT signaling pathway which may impact on 17,20 lyase activity. We conclude that while the triggers for the onset of ZR function in all three species show clear differences (age, stage of development, social status, gender), there are still common mechanisms driving an increase in DHEA biosynthesis in each case. A full understanding of the mechanisms that control 17,20 lyase function and dysfunction in humans may best be achieved by comparative studies of the endocrine mechanisms controlling adrenal ZR function and dysfunction in these nonhuman primate species.     

Immunologic classification of leukemia and lymphoma

Important insights into leukocyte differentiation and the cellular origins of leukemia and lymphoma have been gained through the use of monoclonal antibodies that define cell surface antigens and molecular probes that identify immunoglobulin and T cell receptor genes. Results of these studies have been combined with markers such as surface membrane and cytoplasmic immunoglobulin on B lymphocytes, sheep erythrocyte receptors on T lymphocytes, and cytochemical stains. Using all of the above markers, it is now clear that acute lymphoblastic leukemia (ALL) is heterogeneous. Furthermore, monoclonal antibodies that identify B cells, such as the anti-B1 and anti-B4 antibodies in combination with studies of immunoglobulin gene rearrangement, have demonstrated that virtually all cases of non-T-ALL are malignancies of B cell origin. At least six distinct subgroups of non-T-ALL can now be identified. T-ALL is subdivided by the anti-Leu-9, anti-Leu-1, and antibodies that separate T lymphocyte subsets into three primary subgroups. Monoclonal antibodies are also useful in the subclassification of non-Hodgkin's lymphoma, and certain distinct markers can be correlated with morphologic classification. The cellular origin of the malignant Reed-Sternberg cell in Hodgkin's disease remains uncertain. A substantial number of investigators favor a myelocyte/macrophage origin based on cytochemical staining; however, consistent reactivity with antimonocyte reagents has not been demonstrated. Although monoclonal antibodies are useful in distinguishing acute myeloid from acute lymphoid leukemias, they have less certain utility in the subclassification of acute myelogenous leukemia (AML). Attempts to subclassify AML by differentiation-associated antigens rather than by the French-American-British (FAB) classification are underway in order to document the potential prognostic utility of surface markers. Therapeutic trials using monoclonal antibodies in leukemia and lymphoma have been reported. Intravenous (IV) infusion of unlabeled antibodies is the most widely used method; transient responses have been demonstrated. Antibodies conjugated to radionuclides have been quite successful in localizing tumors of less than 1 cm in some studies. Therapy trials with antibodies conjugated to isotopes, toxins, and drugs are currently planned. Purging of autologous bone marrow with monoclonal antibodies and complement in vitro has been used in ALL and non-Hodgkin's lymphoma; preliminary data suggest that this approach may be an effective therapy and may circumvent many of the obstacles and toxicities associated with in vivo monoclonal antibody infusion.     

In vitro immunization for the production of antibodies to tetanus toxin and toxoid. 2. Antibody production in lymphocyte cultures

The aim of this work was to optimize the antigen-specific prestimulation of human lymphocytes for further hybridization to produce human monoclonal antibodies. In vitro stimulation of human peripheral blood lymphocytes with purified Tetanus Toxoid (TT) resulted both in an increased amount of secreted specific antibodies and in an enhancement of the portion of anti-TT antibodies in the level of total immunoglobulin secretion. Both IgG and IgM antibodies were found. Donors who had not been boostered in vivo with TT for more than 10 years also showed an antibody response to the antigen in vitro. Five days after in vivo boostering we found in lymphocyte cultures derived from 3 donors an enhanced antibody synthesis in the response to TT and also an increased portion of specific antibodies in the spontaneously secreted immunoglobulin in unstimulated control cultures.     

Significance of anti-lymphocyte antibodies in systemic lupus erythematosus

Sera from patients with SLE frequently contain IgM and IgG antibodies with multiple specificities for lymphocyte surface determinants, including autologous antigens. The IgM antibodies are of relatively low binding avidity and exhibit broad reactivity with B and T lymphocytes from most individuals. IgG antibodies are reactive selectively with PBL from different individuals and appear to be more specific for B cell and a minor proportion of T cells. The molecular nature of the surface determinants involved and their relationship with known antigens and receptors remain largely undefined. Interest in anti-lymphocyte antibodies in SLE relates in part to data suggesting a causal role in the abnormal immune system function in this disorder. In this regard, possible mechanisms that are supported by indirect data include: a) antibody-mediated lymphocyte depletion in vivo, perhaps involving functional subsets specifically; b) antibody blockade of surface receptors operant in cell-cell and in cell-soluble antigen interactions. Certain data have raised the possibility that anti-lymphocyte antibodies represent serum markers for infection with virus as etiologic in SLE, but this question is controversial. Nevertheless, further investigation may yet reveal viral or genetically determined “SLE-specific” lymphocyte surface antigens. Clinically, anti-lymphocyte antibodies may have potential for mediating tissue injury in SLE, either directly or indirectly as circulating complexes in association with “shed” lymphocyte surface antigen. Direct evidence in support of such a role in the natural history of this disorder has not been forthcoming.