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The human T lymphotropic viruses (HTLV) are a family of retroviruses which replicate using the enzyme reverse transcriptase. The manifesta- tions of their infections range from no known disease (with HTLV-lV) to fatal acquired immune deficiency syndrome (AIDS, linked to HTLV-III infection). In a similar fashion, de- ficiencies in certain human leukocyte surface antigens (MHC antigens, or adhesion antigens) may be symp- tomless or severe, life-threatening diseases. AIDS, HTLV-l-associated adult T-cell leukemia (ATL), bare lym- phocyte syndrome (BLS) and ad- hesion antigen deficiency syndromes were discussed at the Congress.

HTLV-llllvirus or lymphadenopathy- associated virus (LAV), more recently termed human immunodeficiency virus (HIV), is causally linked with AIDS. Its effects on immune re- sponse are exerted through its ability to infect and kill selectively cells bearing CD4 antigen (predominantly CD4 + helper/inducer phenotype T cells, but macrophages, B cells, and microglial brain cells as well). Mac- rophages may be the earliest target of HIV infection, preceding even CD4 + T cells. The presence of CD4 antigen on microglia would explain the frequency of neurological symp- toms of HIV infection before evi- dence of immunodeficiency appears. HIV does not infect neurones. The use of RNA probes has shown that during the early stages of HIV infec- tion, approximately I in 100 to I in 100 000 CD4 + T cells are infected with HIV (A. Fauci, Bethesda); however, the normal turnover and production of lymphocytes by the bone marrow should be able to re- plenish the infected cells. There may therefore be mechanisms other than a direct cytopathic effect of HIV which induce immunodeficiency in AIDS. These may include: (I) selec- tive depletion of a subset of CD4 ÷ T cells that is crucial to the mainte- nance of the entire T-cell pool; (2) induction of soluble substance(s) with toxic effects on lymphocytes (for example viral protein itself); and (3) autoimmune phenomena (for ex- ample anti-lymphocyte antibodies). According to Fauci HIV can induce B-cell proliferation in the absence of any mitogenic signal and can also induce B-cell differentiation. This would explain, at least in part, the immunological paradox that hyper- immunoglobulinemia is seen along- side low T helper and increased sup-

Immunology Today, voL 7, No. 11, 1986

Primary and acquired immunodeficiency disorders

pressor T-cell numbers and functions in AIDS. The receptor or binding sites for HIV on B cells need to be investi- gated. Furthermore it is interesting to examine whether HIV induces the production of B-cell stimulating fac- tors (BSFs) by infected B cells.

The mechanism(s) and the gene(s) involved in the direct cytotoxicity of CD4 + cells by HIV continue to be explored. HIV is integrated into host cells as a 'provirus' and remains 'silent' until immune activation occurs. There are eight distinct genes in HIV. The tat gene is crucial as a posttranscriptional regulator of viral protein and therefore of viral replica- tion. Tat is fundamental to CD4 + T-cell killing but the study of the XI0. I variant of HIV has shown that tat itself is not responsible for T-cell killing by HIV but still could be an important enhancer or potentiator (R. Gallo, Bethesda). Using this variant of HIV, Gallo and his associ- ates have shown that the 3'-orfgene of HIV is not required for cyto- pathogenicity or replication of HIV. The role of the env gene of HIV in direct CD4 + cell killing remains to be evaluated. Some part of the en- velope is involved in multinucleated giant cell formation and destruction. The relationship of HIV to malignan- cy is not clear because HIV appears not to cause maligancy directly.

Anti-Tac therapy In contrast to HIV, HTLV-I is asso-

ciated with malignant expansion of CD4 + T cells in ATL. Nevertheless HTLV-I does not use the CD4 antigen as its receptor/binding site. HTLV-I is not required to maintain the expan- sion of CD4 ÷ T cells in ATL once it has begun. The tat gene of the retro- virus makes nucleoproteins that are important in turning on viral genes as well as genes for interleukin 2 (IL-2) and IL-2 receptors. A large number of IL-2 receptors are consti- tutively expressed on ATL cells and have been used as a target for ther- apy in patients with ATL. The first clinical trial of unmodified anti-Tac monoclonal antibody, directed at IL- 2 receptors, in the treatment of ATL has resulted in temporary partial or

Sudhir Gupta complete remission (T. Waldmann, Bethesda). None of the five patients treated produced antibodies to mouse immunoglobulin or to the idiotype of the anti-Tac monoclonal antibody. Pseudomonas exotoxin (PE)-conjugated anti-Tac treatment of ATL reduced leukemic cell num- bers but antibodies to PE developed. Anti-Tac antibody bound to IL-2 re- ceptors on leukemic cells is internal- ized slowly into coated pits and then endosomic vesicles. However, the toxin conjugates do not pass easily from the endosome to cytosol. Therefore, a 212bismuth anti-Tac conjugate was developed to circum- vent this limitation. Alpha radiation of HUT I02-B2 cells which have bound 212bismuth anti-Tac elimin- ates more than 98% of their prolif- erative capacity, with only a modest effect on cell lines with no IL-2 re- ceptors. This specific cytotoxicity is blocked by excess unlabeled anti-Tac but not by human IgG. Thus, 212bismuth anti-Tac is a potentially effective and specific immunocyto- toxic agent for the elimination of IL-2 receptor bearing cells.

Anti-Tac antibody also has a potential therapeutic role in other patients with an increased number of Tac ÷ cells. In aplastic anemia, Tac ÷ cells inhibit hematopoiesis and treatment with anti-Tac antibody may therefore inhibit the generation of activated suppressor cells. Anti- Tac antibody may be used in organ transplantation to inhibit the prolif- eration of host T cells in response to foreign MHC antigens present on the donor organs, and to prevent the generation of cytotoxic T cells. In rodent studies, anti-IL-2 receptor antibody treatment has prolonged renal and cardiac and allograft sur- vival. Anti-IL-2 receptor antibody might also have potential in the treatment of certain autoimmune disorders in which autoreactive acti- vated T cells have a role.

Bare lymphocyte syndrome Bare lymphocyte syndrome (BLS)

was first described in 1974 in an infant lacking MHC class I antigens on lymphocytes and platelets. Since then more than 25 patients have

~) 1986, Elsevier Science Publishers B.V., Arnsterdarn 0167-4919/86/$02.00

Immunology Today, voL 7, No. 1 I, 1986 i

been reported and show a remark- able heterogeneity in the degree of deficiency of class I and/or class II antigens and in clinical manifesta- tions: these range from minimal or no immune deficiency (associated with decreased expression of MHC antigens) to severe combined im- mune deficiency (associated with complete lack of class I and/or class II antigens). In BLS II, class II antigens are absent from the surface of B cells, macrophages, Langerhans' cells, Epstein-Barr virus transformed B-cell lines and phytohemagglutinin- induced T-cell blasts. Most of these patients have normal numbers of lymphocytes and T3 + cells, a normal response to mitogens and allo- antigens, and normal cytotoxic T cell function; however, delayed cutaneous hypersensitivity, antigen- specific T-cell proliferation and spe- cific antibody response are lacking (G. Griscelli, Paris). The disease is characterized by a lack of sensitiza- tion and cell--cell interactions. Re- ceptors for interferon (IFN)--y are nor- mal and respond to IFN-~/ by the induction of class I antigens but not of class II antigens, mRNAs for DRy, DRIs, DPIs, and DQIs chains are pre- sent. mRNA for class I antigen is also present. Family studies have shown that the disease is caused by an abnormal regulatory gene(s) that is outside chromosome 6.

Adhesion proteins A family of adhesion proteins

comprised of three surface antigens (CR3, LFA-1 and P150,95) has been identified on both human and murine leucocytes. These share a common 13-chain structure which is linked noncovalently to one of three distinct c~-chain types. (T. Springer, Boston). A complete or partial de- ficiency of CR3/LFA 1/p150,95 has been described. As a rule, patients with total deficiency have more ser- ious life-threatening infections than those with partial deficiency. The disease is characterized by delayed detachment of umbilical cord and omphalitis, pneumonia, necrotic skin infections without pus, oral infec- tions and chronic gingivitis. A consis- tent finding in all patients tested is the greatly reduced phagocytic and respiratory burst response to un- opsonized zymosan or glucan parti- cles derived from yeast. Patients with total deficiency of CR3/LFA 1/ p150,95 exhibit abnormal adher- ence and chemotaxis of neutrophils.

The laboratory findings in patients and family members and the exist- ence of patients who are either total- ly or partially deficient in all of the antigens, suggest that there is more than one type of genetic lesion among the different, pedigrees (autosomal recessive, autosomal codominant). Biosynthetic studies of CR3 and LFA I have shown that c~- and 13-chains are synthesized separ- ately, glycosylated and joined together prior to membrane inser- tion. The molecular basis of the de- ficiency of CR31LFA I ip i 50,95 might be the inability to synthesize 13-chain or the synthesis of abnormal 13-chain that cannot join with n-chain. One patient with complete deficiency has been successfully treated with mis- matched bone marrow transplanta- tion with partial chimera (Griscelli). Since LFA I antigen is not expressed on stem cells, anti-LFA antibody may be usable in the prevention of graft failure.

It is clear that more must be

Autoimmune disorders

Many of the questions about auto- activity raised in 1983 at the last international congress in Kyoto are still pertinent in 1986, but are being analysed at a different level. In 1983, work had begun on the delineation of the nature of the inflammatory infiltrate in autoimmune diseases; this has now extended, through functional and molecular analysis at a clonal level.

Several groups have produced T-cell clones from the thyroids of patients with autoimmune thyroid disease. On balance, functional and phenotypic analyses suggest that T-cell clones from the thyroids of patients with Hashimoto's thyroiditis are largely cytotoxic whereas those from Graves' disease thyroids show a predominance of T helper cells (W. MacKenzie, Toronto). Although some of the cytolytic clones had NK activity, a high proportion (>50%) were OKT4+8 - (G. Canonica, Genoa), thus emphasizing the limita- tions of simple phenotypic analysis as an assessment of function. It may be significant that cells of the helper phenotype can make lymphokines

(~) 1986, Elsevier Science Publishers B.V., Amsterdam 0167 4919/86/$02.00

learned about the role of various genes and gene products responsi- ble for the cytopathic effect of HIV and the additional mechanisms re- sponsible for immunodeficiencies in HIV infection. From this knowledge may come a safe and effective vac- cine for prevention of HIV infection. Anti-retroviral and immunostimula- tory approaches are needed for the treatment of those already exposed to HIV. The value of anti-IL-2 recep- tor monoclonal antibodies conju- gated to radioisotopes in the treat- ment of ATL is already apparent. The experimental use of anti-IL-2 recep- tor antibody in organ transplantation is promising and could be extended to clinical transplantation. Further definition of the molecular basis for inherited deficiencies of protein adhesion antigens is urgently needed.

Division of Basic and Clinical Immunology, University of California, Irvine, California 92717, USA

Anne Cooke, D. Rayner and P. Lydyard

including interferon-~/ (IFN-~I) and lymphotoxin. From the BB rat, an animal model of insulin-depend- ent diabetes mellitus (IDDM), G. Prud'homme (Montreal) has isolated T-cell lines reactive with islet-cell antigens which are restricted to RTI.D-encoded class II MHC deter- minants and are thought to be T helper cells: there was no evidence for functional islet-specific cytolytic T cells in this model. However, Lyt 2 + T-cell clones from NOD mice in- hibited glucose-stimulated insulin release from mouse islets in vitro (M. Hattori, Boston). The molecular means by which islet cell damage is mediated remains unclear, although evidence has been presented for a cytotoxic effect of IL-I on pan- creatic beta cells (K. Bendtzen, Copenhagen).

Another major change since 1983 has been the availability of recom- binant cytokines such as IFN--/, inter- leukin (IL-I), and tumour necrosis fac- tor (TNF), which has allowed careful analysis of the role that these pro- ducts may play in mediating the des- tructive interaction between in

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